| *608750 | ||||||||||||||||||
| ALG3, S. CEREVISIAE, HOMOLOG OF; ALG3 | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| NOT56-LIKE PROTEIN; NOT56L | ||||||||||||||||||
| HGNC Approved Gene Symbol: ALG3 | ||||||||||||||||||
| Cytogenetic location: 3q27.1 Genomic coordinates (GRCh37): 3:183,960,116 - 183,967,312 (from NCBI) | ||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||
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| TEXT | ||||||||||||||||||
| Cloning | ||||||||||||||||||
| Korner et al. (1999) noted that the human Not56-like protein (GenBank Y09022) shares with the yeast ALG3 protein 30% sequence homology, the C-terminal -KKXX ER-retrieval signal, and multiple membrane-spanning helices. Complementation of the glycosylation defect in a yeast strain with a disrupted ALG3 gene by the human Not56-like protein gene demonstrated that NOT56L is the ortholog of the S. cerevisiae ALG3 gene. | ||||||||||||||||||
| Mapping | ||||||||||||||||||
| The International Radiation Hybrid Mapping Consortium mapped the NOT56L gene to chromosome 3 (stSG39280). | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| In a patient with congenital disorder of glycosylation type Id (CDG1D; 601110) reported by Stibler et al. (1995), Korner et al. (1999) identified a homozygous mutation in the ALG3 gene (608750.0001). In a patient with CDG Id, Denecke et al. (2004) identified a silent mutation in the ALG3 gene, resulting in a 37-bp deletion (608750.0002). | ||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||
| Table View | ||||||||||||||||||
| .0001 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id | ||||||||||||||||||
| ALG3, GLY118ASP [dbSNP:rs28940588] | ||||||||||||||||||
| In a patient with CDG Id (601110) reported by Stibler et al. (1995), Korner et al. (1999) identified a 353G-A transition in the ALG3 gene, resulting in a gly118-to-asp (G118D) substitution. The mutation apparently reduces but does not abolish the mannosyltransferase activity. Sequencing of genomic DNA showed that the patient was homozygous for the mutation and that his parents were heterozygous. At the time of the report by Korner et al. (1999), the patient was 5 years of age and suffered from tetraspastic paresis, a severe psychomotor handicap, and multiple dysmorphisms including microcephaly, dysplastic ears, atrophy of the optic nerve, and coloboma of the iris. The epilepsy was reasonably well controlled by valproic acid. | ||||||||||||||||||
| .0002 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id | ||||||||||||||||||
| ALG3, 37-BP DEL, NT160 | ||||||||||||||||||
| In an Italian patient with CDG Id (601110), Denecke et al. (2004) identified a homozygous silent mutation in exon 1 of the ALG3 gene, 165C-T, resulting in a 37-bp deletion in the corresponding transcripts (160del36) due to the activation of a cryptic donor splice site. The deletion resulted in a premature termination codon encoding a protein truncated after the first N-terminal transmembrane domain. Nonsense-mediated decay (NMD) of mRNA is a general mechanism for clearing of RNA molecules containing suitable premature termination codons. However, suppression of NMD using cycloheximide had no influence on ALG3 transcript levels, although the premature termination codons of the transcript fulfill the criteria for the initiation of NMD. Denecke et al. (2005) provided a detailed clinical description of the patient reported by Denecke et al. (2004). | ||||||||||||||||||
| .0003 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id | ||||||||||||||||||
| ALG3, ARG171GLN [dbSNP:rs119103236] | ||||||||||||||||||
| In a patient with a severe phenotype of CDG Id (601110), Sun et al. (2005) detected homozygosity for a G-to-A transition at nucleotide 512 in exon 4 of the ALG3 gene, resulting in an arg172-to-gln (R172Q) substitution. The patient, whose parents were from the Dominican Republic, died at 19 days of age. Hyperinsulinemic hypoglycemia was present, and autopsy revealed islet cell hyperplasia with increased beta-cell mass. Other features were Dandy-Walker malformation, facial dysmorphism, and profound hypotonia. Sun et al. (2005) noted that hyperinsulinemic hypoglycemia had not previously been reported in CDG Id. Lentiviral complementation with wildtype ALG3 corrected the biochemical defect in the patient's fibroblasts. Sun et al. (2005) stated that a substantial portion of both patient and control mRNA transcripts contained the 37-bp deletion (601110.0002). | ||||||||||||||||||
| .0004 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id | ||||||||||||||||||
| ALG3, TRP71ARG [dbSNP:rs119103237] | ||||||||||||||||||
| In 2 sibs with CDG Id (601110), Kranz et al. (2007) identified compound heterozygosity for 2 mutations in the ALG3 gene: a 211T-C transition resulting in a trp71-to-arg (W71R) substitution and a 470T-A transversion resulting in a met157-to-lys (M157K; 608750.0005) substitution. Both mutations occurred in a region that faces the luminal side of the endoplasmic reticulum and may disrupt proper folding. The patients were severely affected with failure to thrive, epilepsy, hypotonia, and significant developmental delay. However, 1 sib had more severe digestive issues, while the other was more neurologically impaired. Transfection of patient fibroblasts with wildtype ALG3 completely restored the defect. | ||||||||||||||||||
| .0005 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id | ||||||||||||||||||
| ALG3, MET157LYS [dbSNP:rs119103238] | ||||||||||||||||||
| See 608750.0004 and Kranz et al. (2007). | ||||||||||||||||||
| REFERENCES | ||||||||||||||||||
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