| *174763 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLYMERASE, DNA, GAMMA; POLG | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLYMERASE, DNA, GAMMA-1; POLG1 POLG, CATALYTIC SUBUNIT POLG-ALPHA; POLGA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: POLG | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 15q26.1 Genomic coordinates (GRCh37): 15:89,859,535 - 89,878,025 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lestienne (1987) provided evidence for a role of DNA polymerase gamma (POLG) in the replication of human mitochondrial DNA. Bertazzoni et al. (1977) showed that the enzyme was present in both the nucleus and the mitochondria. Mitochondrial POLG is a homotetramer; see POLG2 (604983). Based on the sequences of the S. cerevisiae and S. pombe Polg genes, Ropp and Copeland (1996) cloned the human and Drosophila POLG genes and a partial chicken Polg cDNA. The human POLG cDNA, isolated from a HeLa cell cDNA library, encodes a predicted 1,239-amino acid protein that is 78% identical to chicken Polg in the polymerase domain. Antibodies against the polymerase domain of human POLG detected a 140-kD mitochondrial protein on Western blots and immunoprecipitated a protein with POLG-like activity from mitochondrial extracts. The authors found a potentially unstable CAG repeat in the first exon of the human POLG gene. Zullo et al. (1997) identified cloned cDNA and genomic sequences as human mitochondrial POLG by homology with the catalytic subunit of yeast mitochondrial DNA polymerase. Lecrenier et al. (1997) cloned a human POLG cDNA by searching for ESTs with homology to yeast Polg (Mip1p). The human and yeast POLG proteins are 43% identical. Human POLG is expressed as a 4.5- to 5.0-kb mRNA that is most abundant in skeletal muscle and heart. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The POLG protein is composed of a C-terminal polymerase ('pol') domain and an amino-terminal exonuclease ('exo') domain. The exo domain increases the fidelity of mitochondrial DNA replication by conferring a proofreading activity to the enzyme (Lamantea et al., 2002). Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that POLG was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that POLG copurified with mtDNA and was a core nucleoid protein. Bogenhagen et al. (2008) confirmed these findings by Western blot analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By FISH, Zullo et al. (1997) mapped the POLG gene to 15q24-q26 and the mouse Polg gene to chromosome 7. Walker et al. (1997) mapped the POLG gene to 15q25 by FISH. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Del Bo et al. (2003) presented evidence suggesting that mutations in the exonuclease domain of POLG, which is responsible for the proofreading activity of the protein, result in a high frequency of randomly distributed rare mtDNA point mutations. Rovio et al. (1999) demonstrated that the common allele for the trinucleotide CAG repeat within the coding sequence of the POLG gene is 10 CAG repeats. This allele is found in different ethnic groups at a uniformly high frequency (0.88) and is absent in only approximately 1% of individuals, suggesting that it may be maintained by selection. Tang et al. (2011) identified mutations in the POLG gene in 136 (5%) of 2,697 patients analyzed because of a wide range of clinical features suggestive of a POLG-related disorder, including lactic acidosis, seizures, ataxia, peripheral neuropathy, developmental delay, myopathy, chronic progressive external ophthalmoplegia, or hepatopathy. Ninety-two patients had biallelic mutations, 3 had heterozygous dominant mutations, and 41 had 1 heterozygous mutation with a second mutant allele unidentified. A467T (174763.0002) was the most common mutation, accounting for 23% of mutant alleles. Male Infertility Rovio et al. (2001) genotyped infertile and control males for POLG CAG-repeat lengths. Using sperm DNA from persons in whom azoospermia was excluded, they found 9 of 99 infertile males (9%) from Finland or England to be homozygous for the absence of the 10 CAG repeat common allele. In contrast, the common allele was present in sperm DNA from all 98 fertile males studied, as well as in all but 6 of 522 healthy controls whose blood DNA was analyzed in parallel. Based on standard Hardy-Weinberg predictions, the 'homozygous mutant' genotype (absence of the common allele, whether or not this reflected homozygosity for a particular mutant allele) should be found in approximately 1.7% of individuals. They found the genotype at a frequency slightly below expectation in the general population, although this deviation was not statistically significant. In contrast, their finding that the 'homozygous mutant' genotype occurred in 9 of 99 infertile but 0 of 98 fertile males was highly significant. They also found a higher frequency of heterozygosity in infertile males (35%) than in fertile males (18%) or in the general population (23%). Some infertile males may be compound heterozygotes, with a second mutation elsewhere in the gene. Infertile males homozygous for the POLG mutant genotype were below the commonly accepted thresholds for at least 2 out of 3 sperm quality parameters. The POLG genotype in blood and sperm was similar in these individuals, thus excluding any effect of de novo tissue-specific mutation. Polyglutamine tracts are commonly regarded as interfaces for protein-protein interactions; thus, a sperm-specific protein could interact with this region of POLG. Given the many rounds of cell division during spermatogenesis and the functional necessity of mtDNA for sperm function, it seems plausible that a suboptimal mtDNA polymerase could result in the accumulation of mtDNA mutations and in failure to complete differentiation. The mutant allele had 11 CAG repeats as the nodal frequency (see Fig. 1 of Rovio et al. (2001)). In a study of 195 infertile patients and 190 normospermic men of Italian origin, Krausz et al. (2004) found the 10 CAG repeat allele of the POLG gene in 85% of infertile and 81% of fertile controls. Mean values of sperm parameters such as sperm count, motility, and morphology did not differ significantly between repeat allele carriers and controls. The authors concluded that their study failed to confirm any influence of the POLG gene polymorphism on the efficiency of spermatogenesis and that analysis of the CAG repeat tract of the POLG gene does not appear to have any clinical diagnostic value. Progressive External Ophthalmoplegia (PEO) Van Goethem et al. (2001) identified a missense mutation (Y955C; 174763.0001) in the polymerase motif B of the POLG gene in a family segregating autosomal dominant progressive external ophthalmoplegia (PEOA1; 157640). A tyrosine at position 955 is highly conserved in DNA polymerases of different species, including the orthologous enzymes in yeast and Drosophila. In 2 families with evidence of autosomal recessive PEO (PEOB; 258450), Van Goethem et al. (2001) found compound heterozygosity for 2 different missense mutations (see 174763.0002-174763.0004) in the POLG gene. Van Goethem et al. (2003) reported compound heterozygosity for 2 mutations in the POLG gene (A467T, 174763.0002 and R627W, 174763.0005) in a patient with the clinical triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459). The finding indicated that SANDO is a variant of autosomal recessive PEO. Winterthun et al. (2005) identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE, 607459). POLG1 is the only polymerase known to be involved in replication of mtDNA. Kollberg et al. (2005) investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Long-range PCR revealed multiple mtDNA deletions in all the patients but not in controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at a very low frequency in patients and controls. Kollberg et al. (2005) concluded that mtDNA point mutations are not directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations. Gonzalez-Vioque et al. (2006) identified mutations in the POLG gene in 6 (25%) of 24 patients with mitochondrial disease and muscle mtDNA deletions. Five patients had PEO; however, 1 patient, who had a mutation which was previously reported as a polymorphism, showed only mild distal muscle atrophy without ophthalmoplegia. Hudson et al. (2006) identified mutations in the POLG gene in 3 (8%) of 38 patients with sporadic PEO. No mutations were identified in the ANT1 (103220) or C10ORF2 (606075) genes. Mitochondrial DNA Depletion Syndrome 4A (Alpers Type) Naviaux and Nguyen (2004) reported 3 patients with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (174763.0002). Naviaux and Nguyen (2005) stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. In 4 patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0006 and 174763.0013). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes. Ferrari et al. (2005) identified mutations in the POLG gene in 8 patients with Alpers syndrome and 1 patient with a nonspecific severe floppy infant syndrome associated with liver failure. Mitochondrial DNA Depletion Syndrome 4B (MNGIE Type) In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) (Vissing et al., 2002), Van Goethem et al. (2003) identified 3 mutations in the POLG gene: T251I (174763.0007), P587L (174763.0011), and N864S (174763.0012). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. In an infant with severe hypotonia, gastrointestinal dysmotility, and mtDNA depletion in muscle, Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene (G848S, 174763.0006 and R227W, 174763.0021). Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. The patient died at age 20 days from respiratory failure. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was confined mainly to the external layer of the muscularis propria. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The most severe manifestations of defects of the POLG protein have been associated with mutations of the 'spacer' region of POLG. Luoma et al. (2005) identified a family segregating 3 POLG amino acid variants: A467T (174763.0002), R627Q, and Q1236H. The first 2 affect the spacer region, and the third is a polymorphism, allelic with R627Q. Three grades of disease severity appeared to correlate with the genotypes. The patient with the most severe outcome, cerebellar ataxia syndrome, had all 3 variants; those with R627Q and Q1236H had juvenile-onset ptosis and gait disturbance; those with a single A467T allele had late-onset ptosis. Biochemical analysis of expressed mutant proteins revealed that the A467T substitution resulted in decreased activity, DNA binding, and processivity of the polymerase. Other pathogenic spacer mutants showed DNA-binding affinities and processivities similar to or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations may extend beyond the basic catalytic functions of POLG. Stewart et al. (2009) identified 27 POLG mutations in 14 probands with a variety of phenotypes, including PEO, Alpers syndrome, and ataxia. All 6 patients with Alpers syndrome carried at least 1 mutation in the linker region of the protein (A467T or W748S; 174763.0013). In a study of the cellular phenotype derived from 24 children with biallelic POLG1 mutations, 21 of whom had a clinical diagnosis of mitochondrial DNA depletion syndrome-4A, manifest as Alpers syndrome, Ashley et al. (2008) found that the cellular mtDNA content reflected the genotype. Those with mtDNA depletion in the liver and/or muscle had at least 1 missense or nonsense mutation in a catalytic domain, either the polymerase or exonuclease region. Four of 12 patients further analyzed showed a progressive, mosaic pattern of mtDNA depletion in fibroblasts, and all had biallelic mutations in catalytic domains. These patients had a severe clinical phenotype with early onset before 1 year of age, hepatic involvement, and death by 16 months of age. Their cells showed respiratory chain defects. Patients with 2 mutations in the linker region of the gene did not show mtDNA depletion and had the mildest phenotype with onset in childhood or adolescence and little liver involvement. The study also found that the average mtDNA content declined with serial passage in cell culture in patients with mtDNA depletion, which Ashley et al. (2008) postulated was a result of mtDNA replication stalling, indicating the requirement for both catalytic actions of POLG1 in mitochondrial replication. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hakonen et al. (2007) demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. The Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. Hakonen et al. (2007) estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D. Similarly, the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype but differed from Belgian and British patients, suggesting that the W748S founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. The common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. There was also evidence of a common founder, possibly of European origin, for the G848S (174763.0006) mutation. The findings suggested that these mutations did not result from recurrent mutation events but were rather caused by spreading of single founder mutations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Trifunovic et al. (2004) created homozygous knockin mice that expressed a proofreading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. The knockin mice developed an mtDNA mutator phenotype with a 3- to 5-fold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced life span and premature onset of aging-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anemia, reduced fertility, and heart enlargement. Trifunovic et al. (2004) concluded that their results provided a causative link between mtDNA mutations and aging phenotypes in mammals. Kujoth et al. (2005) demonstrated that the mice generated by Trifunovic et al. (2004) (D257A mice) accumulated mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cell turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Kujoth et al. (2005) concluded that accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging. Miller (2005) and Gershon (2005) questioned whether the phenotype of aging described by Kujoth et al. (2005) was really an accelerated aging phenotype. Some of the mice exhibited severe anemia and loss of intestinal crypt cells not commonly seen in aged mice. Prolla and Weindruch (2005) commented that hearing loss and sarcopenia as seen in the D257A mice are commonly observed in aging and that the more severe phenotype such as anemia and loss of intestinal crypts are likely to be secondary to complete stem cell depletion, which is not observed in normal aging. Hance et al. (2005) demonstrated that PolgA deficiency in mouse embryos caused an early developmental arrest between embryonic days 7.5 and 8.5 associated with severe mtDNA depletion. PolgA +/- mice had half the wildtype levels of PolgA transcripts and a slight reduction in mtDNA levels, but developed normally. PolgA transcripts in PolgA +/- mice increased in response to artificially elevated mtDNA copy number, revealing a possible regulatory link between mtDNA maintenance and PolgA expression. Hance et al. (2005) concluded that Polg indeed is the only DNA polymerase capable of maintaining mtDNA in mammalian mitochondria, and appears to be essential for the organogenesis during mammalian embryonic development. Vermulst et al. (2008) identified mitochondrial DNA deletions as a driving force behind the premature aging phenotype of the mitochondrial mutator mice developed by Trifunovic et al. (2004). Vermulst et al. (2008) provided evidence for homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mitochondrial DNA deletions. In addition, their results demonstrated that the rate at which mitochondrial DNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis. Mitochondrial mutator mice showed a 7- to 11-fold increase in mitochondrial DNA deletions over those in wildtype mice or mice heterozygous for this PolgA mutation. Vermulst et al. (2008) found that duodenum, heart, and brain tissue from prematurely aging PolgA homozygous mutator mice contained many COX-negative cells. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT, 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, TYR955CYS [dbSNP:rs113994099] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a 3-generation Belgian pedigree with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (157640), Van Goethem et al. (2001) identified a 2864A-G transition in the POLG gene, resulting in a tyr955-to-cys (Y955C) substitution in the polymerase B domain of the protein. The tyrosine at codon 955 is highly conserved. Segregation analysis showed complete cosegregation of Y955C with autosomal dominant PEO (maximum lod = 4.01 at theta = 0.0). The mutation was present in the 8 patients and 2 of 15 at-risk individuals; it was absent in 432 control chromosomes. Lamantea et al. (2002) identified the heterozygous Y955C mutation in 5 unrelated families with adPEO. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by Zeviani et al. (1989) and Servidei et al. (1991). Microsatellite analysis did not identify a common disease haplotype in these families. To analyze the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis, Ponamarev et al. (2002) expressed the Y955C mutant protein in Sf9 cells by site-directed mutagenesis. The Y955C enzyme retained a wildtype catalytic rate and demonstrated a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate, but the authors noted that mitochondrial matrix pools are usually high enough to overcome this reduced affinity. Fidelity studies showed that the Y955C derivative was 2-fold less accurate for basepair substitutions than wildtype, even with proofreading activity. Genetic inactivation of the exonuclease revealed a 10- to 100-fold increase in mismatch errors. Ponamarev et al. (2002) presented a model in which the enhanced error rate of the mutant enzyme promotes mtDNA deletions, as seen in PEO, via a slippage mechanism. In affected members of 4 adPEO families, including the Swedish family originally reported by Lundberg (1962), Luoma et al. (2004) identified the heterozygous Y955C mutation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS, INCLUDED SPINOCEREBELLAR ATAXIA WITH EPILEPSY, INCLUDED MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ALA467THR [dbSNP:rs113994095] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a family with 3 affected sibs with autosomal recessive PEO (258450), Van Goethem et al. (2001) identified compound heterozygosity for 2 missense mutations in the POLG gene: a 1399G-A transition, resulting in an ala467-to-thr (A467T) substitution, and a 911T-G transversion, resulting in a leu304-to-arg substitution (L304R; 174763.0003). In 2 affected individuals in another family, Van Goethem et al. (2001) identified the A467T mutation in compound heterozygous state with an 8G-C transversion, resulting in an arg3-to-pro substitution (R3P; 174763.0004). Three of 229 control individuals were heterozygous for A467T (allele T frequency of 0.6%). The R3P mutation was not observed in any of the control individuals. The A467T mutation occurs in the linker region of the protein (Stewart et al., 2009). Van Goethem et al. (2003) stated that the A467T mutation has a frequency of 0.6% in the Belgian population and that sensory neuropathy is the initial feature in Belgian compound heterozygous autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation in combination with another mutation. Van Goethem et al. (2003) reported a patient who was homozygous for the A467T mutation, which they incorrectly reported as ALA476THR. (Van Broeckhoven (2004) reported the correct mutation as A467T.) At age 15 years, the patient experienced mild ataxia, and later developed myoclonus, seizures, and sensory neuropathy. External ophthalmoplegia was absent on repeated examinations. Muscle biopsy did not show any abnormalities, including no ragged-red fibers, but long-range PCR detected a low proportion of mtDNA deletions in the patient's muscle. Van Goethem et al. (2003) noted that the clinical features in this patient were unique and suggested that some features overlapped with the syndrome of myoclonus, epilepsy, and ragged-red fibers (MERRF; 545000). In 3 sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (607459) originally reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified homozygosity for the A467T mutation. An unrelated British patient was compound heterozygous for the A467T mutation and W748S (174763.0013). An unrelated Belgian patient with a variant form of SANDO without ophthalmoparesis was also homozygous for the A467T mutation. That patient had psychiatric symptoms, severe gastroparesis, and dilated cardiomyopathy, illustrating the variable clinical phenotype that can result from recessive POLG mutations. In 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Naviaux and Nguyen (2005) identified compound heterozygosity for 2 mutations in the POLG gene: A467T and E873X (174763.0008). An earlier report on these patients by Naviaux and Nguyen (2004) had incorrectly stated that they were homozygous for the E873X mutation. In 2 sisters with mtDNA depletion syndrome manifest as Alpers syndrome, Nguyen et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: a A467T and W1020X (174763.0017). Two affected sibs from another family with Alpers syndrome were compound heterozygous for A467T and G848S (174763.0006). Another child with Alpers syndrome from an unrelated family who was homozygous for the A467T mutation showed late-onset at age 8.5 years and death by age 9 years. Winterthun et al. (2005) identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Hakonen et al. (2007) demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. Further analysis indicated that the Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. Hakonen et al. (2007) estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, LEU304ARG [dbSNP:rs121918044] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0002 and Van Goethem et al. (2001). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ARG3PRO [dbSNP:rs121918045] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0002 and Van Goethem et al. (2001). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ARG627TRP [dbSNP:rs121918046] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a sporadic case of SANDO (607459), Van Goethem et al. (2003) found compound heterozygosity for 2 mutations in the POLG gene: A467T (174763.0002) and arg627-to-trp (R627W). The R627W mutation came from the father, and the A467T mutation from the mother. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS,
DIGENIC, INCLUDED MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, GLY848SER [dbSNP:rs113994098] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with autosomal recessive PEO (258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; 174763.0007). In a patient with PEO, Van Goethem et al. (2003) identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; 606075.0008), indicating a digenic mode of inheritance. In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (174763.0013). All patients died in childhood. Davidzon et al. (2005) noted that the G848S mutation occurs within the polymerase motif C of the enzyme. Nguyen et al. (2005) reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (174763.0002), and the other was compound heterozygous for G848S and W748S. Hakonen et al. (2007) presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. In an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; 174763.0021) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was mainly confined to the external layer of the muscularis propria. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, THR251ILE [dbSNP:rs113994094] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0006 and Lamantea et al. (2002). In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662), manifest as a neurogastrointestinal encephalopathy syndrome (Vissing et al., 2002), Van Goethem et al. (2003) identified 3 mutations in the POLG gene: a 752C-T transition in exon 3, resulting in a thr251-to-ile (T251I) substitution, a 1760C-T transition in exon 10, resulting in a pro587-to-leu substitution (P587L; 174763.0011), and a 2591A-T transversion in exon 16, resulting in an asn864-to-ser substitution (N864S; 174763.0012). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. Lamantea and Zeviani (2004) identified the T251I mutation and the P587L mutation on the same allele in 3 families with autosomal recessive PEO (258450); each of the families was compound heterozygous for another POLG1 mutation in trans with the 2 cis alleles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, GLU873TER [dbSNP:rs121918047] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Naviaux and Nguyen (2004) identified compound heterozygosity for 2 mutations in the POLG gene: a 2899G-T transversion in exon 17 of the POLG gene, resulting in a glu873-to-ter (E873X) mutation, and A467T (174763.0002). In the late stages of the disease, POLG activity was less than 5% of normal and mitochondrial DNA was depleted. An earlier report on these patients by Naviaux and Nguyen (2004) had incorrectly stated that they were homozygous for the E873X mutation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, HIS932TYR [dbSNP:rs121918048] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 Italian sibs with SANDO (607459), Mancuso et al. (2004) identified compound heterozygosity for 2 mutations in the POLG gene: a 2794C-T transition in exon 18, resulting in a his932-to-tyr (H932Y) substitution, and a 3151G-C transversion in exon 20, resulting in a gly1051-to-arg (G1051R; 174763.0010) substitution. Neither mutation was identified in 120 control alleles. Both mutations occur in highly conserved residues of the POLG gene that encode the polymerase region. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, GLY1051ARG [dbSNP:rs121918049] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0009 and Mancuso et al. (2004). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, PRO587LEU [dbSNP:rs113994096] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0007 and Van Goethem et al. (2003). Filosto et al. (2003) identified the P587L mutation in 2 sibs with PEO, exercise intolerance, distal limb weakness, and peripheral neuropathy. One of the sibs also had abdominal cramping and gastrointestinal dysmotility suggesting MNGIE syndrome (603041). An unrelated patient with the P587L mutation had progressive hearing loss, ataxia, PEO, distal myopathy, and hypogonadism. Lamantea and Zeviani (2004) identified the P587L mutation and the T251I mutation (174763.0007) on the same allele in 3 families with autosomal recessive PEO (258450); each of the families was compound heterozygous for another POLG mutation in trans with the 2 cis alleles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0012 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ASN864SER [dbSNP:rs121918050] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0007 and Van Goethem et al. (2003). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0013 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SPINOCEREBELLAR ATAXIA WITH EPILEPSY, INCLUDED MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, TRP748SER [dbSNP:rs113994097] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (174763.0002). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. Van Goethem et al. (2004) concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear. In a follow-up report of the family reported by Rantamaki et al. (2001) and Van Goethem et al. (2004), Rantamaki et al. (2007) found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers. Hakonen et al. (2005) found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes. Winterthun et al. (2005) identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; 174763.0016). In 4 children with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (174763.0006). All patients died in childhood. Nguyen et al. (2005) reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S. Hakonen et al. (2007) demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. Hakonen et al. (2007) estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0014 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT, 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ALA957SER [dbSNP:rs121918051] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of 2 PEOA1 (157640) families originating from a small village in northwest Sicily, Lamantea et al. (2002) identified a heterozygous 2869G-T transversion in the POLG gene, resulting in an ala957-to-ser (A957S) substitution. One patient in 1 of the families was homozygous for the A957S mutation and showed a more severe phenotype with earlier onset and a much higher amount of mtDNA deletions than his mildly affected heterozygous mother. Microsatellite analysis showed a common disease haplotype, supporting a common origin in these 2 families. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0015 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT, 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, TYR831CYS [dbSNP:rs41549716] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sibs with early-onset parkinsonism and PEOA1 (157640), Mancuso et al. (2004) identified a heterozygous 2492A-G transition in exon 16 of the POLG gene, resulting in a tyr831-to-cys (Y831C) substitution. Parkinsonism was a prominent feature in both patients. Luoma et al. (2007) identified the Y831C substitution in 5 controls, suggesting that it is a polymorphism. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0016 SPINOCEREBELLAR ATAXIA WITH EPILEPSY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, GLN497HIS [dbSNP:rs121918052] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459), Winterthun et al. (2005) identified a homozygous 1491G-C transversion in the POLG gene, resulting in a gln497-to-his (Q497H) substitution. Both patients were also homozygous for another disease-causing POLG mutation (W748S; 174763.0013). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0017 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, TRP1020TER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sisters with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Nguyen et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: a 3339G-A transition in exon 19, resulting in a trp1020-to-ter (W1020X) substitution, and A467T (174763.0002). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0018 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ARG853TRP [dbSNP:rs121918053] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 Italian sisters with early-onset parkinsonism, peripheral sensory neuropathy, and mitochondrial DNA deletions but without PEO (258450), Davidzon et al. (2006) identified compound heterozygosity for 2 mutations in the POLG gene: a 2839C-T transition in exon 16 resulting in an arg853-to-trp (R853W) substitution and a 2491G-C transversion in exon 13 resulting in a gly737-to-arg (G737R; 174763.0019) substitution. The R853W and G737R substitutions occurred in the polymerase domain and the linker region, respectively. Each unaffected parent was heterozygous for 1 of the mutations. Despite the absence of PEO, the phenotype was most consistent with the clinical features of that disorder. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0019 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, GLY737ARG [dbSNP:rs121918054] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0018 and Davidzon et al. (2006). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0020 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT, 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, SER511ASN [dbSNP:rs121918055] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 6 affected members of a large family with autosomal dominant PEO with mitochondrial DNA deletions (157640), Hudson et al. (2007) identified a heterozygous 1532G-A transition in exon 8 of the POLG gene, resulting in a ser511-to-asn (S511N) substitution in the linker region of the protein. The substitution was not identified in 192 control chromosomes or 248 disease control subjects. The S511N pathogenic mutation was found on the same allele as an intronic variant (2070+158G-A), which the authors considered unlikely to have functional consequences. All patients had ptosis, and 1 had external ophthalmoplegia. The 69-year-old asymptomatic sister of the index patient also carried the S511N mutation, suggesting incomplete penetrance. The female index patient had ataxia, hearing loss, and sensory axonal neuropathy. Her son also had hearing loss and parkinsonism and was found to have a second POLG variant (1389G-A) on the other allele, but both his carrier sister and obligate carrier father had no reported neurologic abnormalities. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0021 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, ARG227TRP [dbSNP:rs121918056] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 174763.0006 and Giordano et al. (2009). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0022 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG, PRO1073LEU | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kurt et al. (2010) identified a 3218C-T transition in exon 20 of the POLG gene, resulting in a pro1073-to-leu (P1073L) substitution, in compound heterozygosity with another pathogenic POLG mutation in 4 patients who all had a hepatocerebral disorder with psychomotor delay, seizures, and liver disease, consistent with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome. The P1073L mutation occurred in a conserved residue in the polymerase domain of the protein. An unrelated girl and boy were compound heterozygous for the P1073L and A467T (174763.0002) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; 613662). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. RT-PCR showed severe mtDNA depletion in liver tissue (72.1% depletion compared to controls). The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for the P1073L and W748S (174763.0013) and G848S (174763.0006) mutations, respectively. The first child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. Muscle tissue showed mtDNA depletion (64%). Kurt et al. (2010) emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the children with the P1073L mutation also had gastrointestinal dysmotility, suggesting that this mutation may be associated with that particular feature. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||