| *607439 | |||||||||||||||||||||||||||
| PROTEIN O-MANNOSYLTRANSFERASE 2; POMT2 | |||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: POMT2 | |||||||||||||||||||||||||||
| Cytogenetic location: 14q24.3 Genomic coordinates (GRCh37): 14:77,741,298 - 77,787,224 (from NCBI) | |||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||
| POMT2 encodes an integral membrane protein of the endoplasmic reticulum (ER) that shares significant sequence similarity with a family of protein O-mannosyltransferases of S. cerevisiae. For additional background information, see POMT1 (607423). | |||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||
| By EST database searching with yeast Pmt sequences as query, Willer et al. (2002) identified POMT2. They assembled a full-length POMT2 cDNA from a from a cerebellum cDNA library. The deduced 750-amino acid protein has a 7-transmembrane helical structure with a central hydrophilic domain flanked by 5 N-terminal and 2 C-terminal transmembrane regions. Like other known members of the Pmt family, it lacks a typical ER-targeting or -retention signal and contains 5 N-glycosylation sites. POMT2 shares 36% sequence identity with human POMT1, 91% with mouse Pomt2, and between 33% and 37% with yeast Pmt enzymes. Phylogenetic analysis revealed closest similarity with the yeast Pmt2 subfamily. RNA dot-blot analysis detected expression of mouse Pomt2 in all tissues examined, with testis showing about 7-fold higher expression than other tissues. Northern blot analysis detected 2 mRNA species of 2.7 kb and 4.7 kb. The shorter transcript was present in all mouse somatic tissues tested. The longer transcript was expressed only in testis and encoded a testis-specific isoform. In situ hybridization and immunolocalization of mouse testis showed that Pomt2 localizes to maturing spermatids and is abundant within the acrosome. Endogenous expression of POMT2 in HEK 293 cells was undetectable; however, following transfection and expression, POMT2 was stably expressed as an 83-kD protein that associated with membranes after cell fractionation. Treatment with endoglycosidase H indicated that at least 2 of the 5 potential N-glycosylation sites are utilized. Immunolocalization revealed strong perinuclear and reticular staining that colocalized with the ER marker protein ERp72 (PDIA4). | |||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||
| Willer et al. (2002) determined that the POMT2 gene contains 21 exons and spans 46 kb. | |||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||
| By genomic sequence analysis, Willer et al. (2002) mapped the POMT2 gene to chromosome 14q24.3. | |||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||
| Mutation in the POMT2 gene can cause 3 different forms of muscular dystrophy-dystroglycanopathy (MDDG): a severe congenital form with brain and eye anomalies (type A2; MDDGA2, 613150), formerly designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB); a less severe congenital form with mental retardation (type B2; MDDGB2; 613156); and a milder limb-girdle form (type C2; MDDGC2; 613158), previously designated LGMD2N. Van Reeuwijk et al. (2005) sequenced the POMT2 gene in 6 unrelated families with Walker-Warburg syndrome (MDDGA1; 613150) and identified homozygous mutations (607439.0001-607439.0003) in 3 families, respectively. Bouchet et al. (2007) identified mutations in the POMT1 gene (607423) in 13 (32%) of 41 families in which at least 1 fetus had severe type II lissencephaly. The minimum diagnostic criteria included hydrocephalus, agyria, thickened leptomeninges filled with neuroglial ectopia, disorganized cortical ribbon, and cerebellar dysplasia. Mutations in the POMGNT1 (606822) and POMT2 genes were identified in 6 (15%) and 3 (7%) families, respectively. Overall, mutations were identified in 22 of 41 families included in the study. Definitive pathogenic mutations were not identified in the FKRP (606596), FKTN (607440), or LARGE (603590) genes. Godfrey et al. (2007) identified POMT2 mutations in 10 of 92 patients with evidence of a muscular dystrophy due to defective glycosylation of alpha-dystroglycan. Seven patients had MEB (MDDGA2; 613150), 2 sibs had congenital muscular dystrophy with mental retardation (MDDGB2; 613156), and 1 had limb-girdle muscular dystrophy (MDDGC2; 613158) (see, e.g., 607439.0004). All had low IQ, and most had structural brain abnormalities. Mercuri et al. (2009) identified POMT2 mutations in 9 (11%) of 81 Italian patients with a dystroglycanopathy. Three patients had normal or minimal changes on MRI, 3 had cerebellar hypoplasia, 2 had MEB, and 1 had Chiari malformation type 1. All had mental retardation, and all but 1 had microcephaly (see, e.g., 607439.0014-607439.0016). No clear-cut genotype-phenotype correlations were observed; however, the more severe phenotypes appeared to be associated with mutations predicted to result in severe disruption of the gene. Yanagisawa et al. (2009) identified 8 different mutations in the POMT2 gene (see, e.g., 607439.0004; 607439.0017-607439.0019) in 5 unrelated patients with congenital muscular dystrophy and mental retardation. Three patients, and the sib of 1 patient, had a more severe phenotype, consistent with MDDGA2, and two had a slightly less severe phenotype without cerebral dysplasia, consistent with MDDGB2. Two of the mutations were deletions involving several exons of the gene and 2 were splice site mutations. Yanagisawa et al. (2009) noted that larger intragenic deletions and splice site mutations may be missed on standard sequencing. | |||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||
| .0001 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, ARG638TER [dbSNP:rs119463989] | |||||||||||||||||||||||||||
| In a Moroccan patient, born of consanguineous parents, with Walker-Warburg syndrome (MDDGA2; 613150), van Reeuwijk et al. (2005) identified homozygosity for a 1912C-T transition in exon 19 of the POMT2 gene, resulting in an arg638-to-ter (R638X) substitution. The mutation was preceded by a known polymorphism, 1911G-T. The mutation was not found in 170 control chromosomes. | |||||||||||||||||||||||||||
| .0002 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, IVS8DS, G-A, +1 | |||||||||||||||||||||||||||
| In a Pakistani patient, born of consanguineous parents, with Walker-Warburg syndrome (613150), van Reeuwijk et al. (2005) identified homozygosity for a G-to-A transition (1005+1G-A) in intron 8 of the POMT2 gene, predicted to result in donor site disruption. The mutation was not found in 290 control chromosomes. | |||||||||||||||||||||||||||
| .0003 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, 1-BP DEL, 1261C | |||||||||||||||||||||||||||
| In 2 sibs with Walker-Warburg syndrome (613150), van Reeuwijk et al. (2005) identified homozygosity for a 1-bp deletion (1261delC) in exon 12 of the POMT2 gene, resulting in a premature stop codon (T433X). The first-cousin Bengali parents were heterozygous for the mutation, which was not found in 140 control chromosomes. | |||||||||||||||||||||||||||
| .0004 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2, INCLUDED | |||||||||||||||||||||||||||
| POMT2, TYR666CYS | |||||||||||||||||||||||||||
| In 2 unrelated patients with congenital muscular dystrophy and severe mental retardation (MDDGB2; 613156), Yanagisawa et al. (2007) identified a homozygous 1997A-G transition in exon 19 of the POMT2 gene, resulting in a tyr666-to-cys (Y666C) substitution in a highly conserved residue. The patients were of Moroccan and French descent, respectively. Haplotype analysis indicated a founder effect. Two additional patients with a similar phenotype were compound heterozygous for Y666C and another pathogenic POMT2 mutation (W647X; 607439.0005 and W748R; 607439.0006). Godfrey et al. (2007) identified a homozygous Y666C substitution in 2 sibs with congenital muscular dystrophy and low IQ. Both patients had onset in infancy and increased serum creatine kinase. One achieved walking, the other sitting. One had contractures, muscle hypertrophy, and microcephaly. The other had hypoplastic cerebellum, micropenis, and cryptorchidism. Godfrey et al. (2007) identified a homozygous Y666C mutation in a patient classified as having muscle-eye-brain disease (613150). The patient reportedly had onset at age 4 years, never achieved walking, had increased serum creatine kinase, muscle hypertrophy, microcephaly, low IQ, and encephalocele. Two additional patients with muscle-eye-brain disease were compound heterozygous for Y666C and another pathogenic POMT2 mutation (see, e.g., R413P; 607439.0007). Mercuri et al. (2009) identified compound heterozygosity for Y666C and G246D (607439.0016) in an Italian patient with congenital muscular dystrophy, microcephaly, mental retardation, but normal brain MRI with minimal white matter changes. Yanagisawa et al. (2009) reported 3 unrelated French patients who were compound heterozygosity for the Y666C mutation and another pathogenic mutation in the POMT2 gene. Two patients with MDDGB2 were compound heterozygous for Y666C and another pathogenic mutation (see, e.g., 607439.0017), whereas the third had the more severe MDDGA2 phenotype and carried Y666C and a deletion of several exons of the POMT2 gene. | |||||||||||||||||||||||||||
| .0005 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| POMT2, TRP647TER | |||||||||||||||||||||||||||
| In a 14-year-old boy with congenital muscular dystrophy and mental retardation (613156), Yanagisawa et al. (2007) identified compound heterozygosity for 2 mutations in the POMT2 gene: Y666C (607439.0004) and a 1941G-A transition in exon 19, resulting in a trp647-to-ter (W647X) substitution. He had congenital hypotonia, contractures, only achieved sitting, had microcephaly, mild myopia, cerebral atrophy, and cerebellar hypoplasia. | |||||||||||||||||||||||||||
| .0006 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| POMT2, TRP748ARG | |||||||||||||||||||||||||||
| In a 6-year-old French boy with congenital muscular dystrophy and mental retardation (613156), Yanagisawa et al. (2007) identified compound heterozygosity for 2 mutations in the POMT2 gene: Y666C (607439.0004) and a 2242T-C transition in exon 21, resulting in a trp748-to-arg (W748R) substitution. He had congenital hypotonia, contractures, only achieved sitting, had microcephaly, mild strabismus, cerebral atrophy, and cerebellar hypoplasia. | |||||||||||||||||||||||||||
| .0007 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, ARG413PRO [dbSNP:rs75122396] | |||||||||||||||||||||||||||
| In a patient with muscle-eye-brain disease (613150), Godfrey et al. (2007) identified compound heterozygosity for 2 mutations in the POMT2 gene: a 1238G-C transversion in exon 11, resulting in an arg413-to-pro (R413P) substitution, and Y666C (607439.0004). Although clinical details were limited, this patient had onset at age 7 months, never achieved sitting, had contractures, hypermetropia, hydrocephalus, brain white matter changes, and cerebellar cysts. | |||||||||||||||||||||||||||
| .0008 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, VAL373PHE | |||||||||||||||||||||||||||
| In a patient with muscle-eye-brain disease (613150), Godfrey et al. (2007) identified compound heterozygosity for 2 mutations in the POMT2 gene: a 1117G-T transversion in exon 10 resulting in a val373-to-phe (V373F) substitution, and a 593T-A transversion in exon 5 resulting in an ile198-to-asn (I198N; 607439.0009) substitution. The patient had onset in the neonatal period, increased serum creatine kinase, achieved sitting only, had contractures, muscle hypertrophy, and scoliosis. Other features included congenital cataracts, low IQ, microcephaly, seizures, brainstem abnormalities, hydrocephalus, and brain white matter changes. | |||||||||||||||||||||||||||
| .0009 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, ILE198ASN | |||||||||||||||||||||||||||
| See 607439.0006 and Godfrey et al. (2007). | |||||||||||||||||||||||||||
| .0010 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 2 | |||||||||||||||||||||||||||
| POMT2, THR184MET | |||||||||||||||||||||||||||
| In a 5-year-old Italian girl with limb-girdle muscular dystrophy (MDDGC2; 613158), Biancheri et al. (2007) identified a homozygous 551C-T transition in exon 5 of the POMT2 gene, resulting in a thr184-to-met (T184M) substitution in a conserved residue in the active site of the protein. The mutation was not found in 200 controls. She showed normal psychomotor development in the first year of life, but learned to walk at age 18 months. Physical examination showed calf hypertrophy, increased serum creatine kinase, and mild muscle weakness. Muscle biopsy showed dystrophic changes, inflammatory changes, and severely decreased alpha-dystroglycan. Brain MRI, ophthalmologic examination, and cognitive development were normal. In a patient with limb-girdle muscular dystrophy, Godfrey et al. (2007) identified compound heterozygosity for 2 mutations in the POMT2 gene: T184M and a 2243G-C transversion in exon 21, resulting in a trp748-to-ser (W748S; 607439.0011) substitution. Although clinical details were limited, the patient had onset at 18 months, achieved walking, had increased serum creatine kinase, muscle hypertrophy, low IQ, and right bundle branch block on echocardiogram. MRI was not performed. | |||||||||||||||||||||||||||
| .0011 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 2 | |||||||||||||||||||||||||||
| POMT2, TRP748SER | |||||||||||||||||||||||||||
| See 607439.0010 and Godfrey et al. (2007). | |||||||||||||||||||||||||||
| .0012 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, GLY353SER | |||||||||||||||||||||||||||
| In a 11-year-old Italian girl with muscle-eye-brain disease (613150), Mercuri et al. (2006) identified compound heterozygosity for 2 mutations in the POMT2 gene: a 1057G-A transition in exon 9 resulting in a gly353-to-ser (G353S) substitution, and a 2177G-A transition in exon 21 resulting in a gly726-to-glu (G726E; 607439.0013) substitution. She was found to have ventricular dilatation and hypoplasia of the cerebellar vermis on prenatal ultrasound at 28 weeks' gestation. After birth, she was hypotonic and never achieved independent sitting. She showed poor growth, respiratory insufficiency, severe mental retardation with only a few words, microcephaly, severe muscle weakness, macroglossia, contractures, and muscle hypertrophy of the lower limbs. Brain MRI showed hypoplasia of the cerebellar vermis and pons, as well as periventricular white matter abnormalities. | |||||||||||||||||||||||||||
| .0013 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, GLY726GLU | |||||||||||||||||||||||||||
| See 607439.0012 and Mercuri et al. (2006). | |||||||||||||||||||||||||||
| .0014 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| POMT2, GLY353SER | |||||||||||||||||||||||||||
| In an Italian patient with congenital muscular dystrophy, cerebellar hypoplasia, microcephaly, and mental retardation (613156), Mercuri et al. (2009) identified compound heterozygosity for 2 mutations in the POMT2 gene: a 1057G-A transition in exon 9 resulting in a gly353-to-ser (G353S) substitution, and a 2177G-A transition in exon 21, resulting in a gly726-to-glu (G726E; 607439.0015) substitution. | |||||||||||||||||||||||||||
| .0015 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| POMT2, GLY726GLU | |||||||||||||||||||||||||||
| See 607439.0005 and Mercuri et al. (2009). | |||||||||||||||||||||||||||
| .0016 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| POMT2, GLY246ASP | |||||||||||||||||||||||||||
| See 607439.0004 and Mercuri et al. (2009). | |||||||||||||||||||||||||||
| .0017 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 2 | |||||||||||||||||||||||||||
| POMT2, IVS1DS, G-C, +5 | |||||||||||||||||||||||||||
| In a 4-year-old French boy with MDDGB2 (613156), Yanagisawa et al. (2009) identified compound heterozygosity for 2 mutations in the POMT2 gene: Y666C (607439.0004) and a G-to-C transversion in intron 1, resulting in abnormal splicing and premature protein truncation. The patient had mental retardation, microcephaly, congenital hypotonia, but could sit unsupported, and increased serum creatine kinase. He had no cerebral dysplasia, and no ocular, brainstem, or cerebellar abnormalities, but imaging showed some white matter abnormalities in the parietal-occipital region. | |||||||||||||||||||||||||||
| .0018 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, IVS12AS, G-A, -14 | |||||||||||||||||||||||||||
| In a 5-year-old Portuguese boy with MDDGA2 (613150), Yanagisawa et al. (2009) identified a homozygous G-to-A transition in intron 12 (133-14G-A) of the POMT2 gene, resulting in the creation of a new splice acceptor site and predicted to insert 4 amino acids between exons 12 and 13. In 2 sibs with MDDGA2 from an unrelated family of Argentinian descent, the authors identified compound heterozygosity for the IVS12 mutation and a 1445G-T transversion, resulting in a gly482-to-val (G482V; 607439.0019) substitution in a conserved residue in the third MIR domain. All 3 patients had microcephaly, severe mental retardation, cerebral dysplasia, cerebellar hypoplasia, and congenital hypotonia with only sitting achieved. | |||||||||||||||||||||||||||
| .0019 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2 | |||||||||||||||||||||||||||
| POMT2, GLY482VAL | |||||||||||||||||||||||||||
| See 607439.0018 and Yanagisawa et al. (2009). | |||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||
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