Alternative titles; symbols
HGNC Approved Gene Symbol: ALG5
Cytogenetic location: 13q13.3 Genomic coordinates (GRCh38) : 13:36,949,738-36,999,367 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q13.3 | Polycystic kidney disease 7 | 620056 | Autosomal dominant | 3 |
The ALG5 gene encodes dolichyl-phosphate beta-glycosyltransferase (EC 2.4.1.117), a transmembrane-bound enzyme of the endoplasmic reticulum (ER) dolichol cycle that is involved in N-glycosylation as a posttranslational modification of many glycoproteins (summary by Lemoine et al., 2022).
By searching EST databases and using low-stringency PCR amplification to screen a human T-lymphocyte cDNA library, Imbach et al. (1999) obtained a complete cDNA encoding the ortholog of S. cerevisiae ALG5. The human ALG5 protein contains 242 amino acids and is 58% similar to yeast ALG5. Northern blot analysis revealed expression of a 1.3-kb ALG5 transcript in pancreas, placenta, liver, heart, brain, kidney, skeletal muscle, and lung.
Gross (2014) mapped the ALG5 gene to chromosome 13q13.3 based on an alignment of the ALG5 sequence (GenBank AF161498) with the genomic sequence (GRCh37).
In 19 patients from 5 unrelated families with polycystic kidney disease-7 (PKD7; 620056), Lemoine et al. (2022) identified heterozygous mutations in the ALG5 gene (see, e.g., 604565.0001-604565.0004). There was 1 frameshift, 1 nonsense, 2 missense, and 1 splice site mutation. The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutations in families 2 and 3 were identified by targeted massively parallel sequencing of 1,213 individuals with kidney disease. The mutations in family 4 and in a singleton (family 5) were found by whole-genome sequencing of 3,520 probands with various renal diseases. The mutations segregated with the disorder in families 1, 2, 3, and 4. In vitro studies of CRISPR/Cas9-mediated biallelic and monoallelic frameshift mutations in the ALG5 gene expressed in renal cortical tubular epithelial (RCTE) cells showed abnormal accumulation of Man9GlcNAc2 lipid-linked oligosaccharide (LLO) precursors and their transfer onto proteins in human kidney cells. Further studies revealed that the lack of N-glycosylation resulted in abnormal maturation of the PKD1 (601313) protein that could be rescued by wildtype ALG5, but not by either of the missense variants. Lack of ALG5 also caused intracellular mislocalization of both PKD1 and PKD2 (173910), and evidence suggested that there was activation of the unfolded protein response (UPR).
In 2 distantly related Irish families (F350 and F200) with a late-onset autosomal dominant polycystic kidney disease-like phenotype and tubulointerstitial fibrosis, Elhassan et al. (2024) identified 23 individuals with a heterozygous R79W mutation in the ALG5 gene (604565.0005). Among these 23 individuals, 18 were clinically affected with a slowly progressive chronic kidney disease. The authors identified abnormal ALG5 distribution in the Golgi apparatus of renal tubular cells. Abnormal accumulation of uromodulin was noted in the endoplasmic reticulum, and decreased plasma and urinary uromodulin levels were also seen in affected persons, suggesting abnormal maturation and trafficking of uromodulin, resulting in structural and functional changes in the kidney.
In 9 patients from a 3-generation family (PK20267, family 1) with polycystic kidney disease-7 (PKD7; 620056), Lemoine et al. (2022) identified a heterozygous 2-bp deletion (c.703_704delCA, NM_013338.5) in the ALG5 gene, predicted to result in a frameshift and premature termination (Gln235ValfsTer21). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Data from the gnomAD database indicate that ALG5 is depleted in predicted loss-of-function variants. Functional studies of the variant and studies of patient cells were not performed.
In 5 affected members of a multigenerational family (PK13924, family 2) with polycystic kidney disease-7 (PKD7; 620056), Lemoine et al. (2022) identified a heterozygous c.773G-A transition (c.773G-A, NM_013338.5) in exon 8 of the ALG5 gene, resulting in a trp258-to-ter (W258X) substitution. The mutation, which was found by targeted massively parallel sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs (PK14384, family 3) with polycystic kidney disease-7 (PKD7; 620056), Lemoine et al. (2022) identified a heterozygous c.635G-A transition (c.635G-A, NM_013338.5) in the ALG5 gene, resulting in an arg212-to-his (R212H) substitution at a conserved residue. The mutation, which was found by targeted massively parallel sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The patients' deceased father died of end-stage kidney disease at age 76; DNA was not available. In vitro functional expression studies showed that the R212H variant was unable to rescue defective glycosylation and maturation of PKD1 (601313), whereas wildtype ALG5 was able to rescue the phenotype.
In a mother and daughter (family 4) with polycystic kidney disease-7 (PKD7; 620056), Lemoine et al. (2022) identified a heterozygous c.623G-A transition (c.623G-A, NM_013338.5) in the ALG5 gene, resulting in an arg208-to-his (R208H) substitution at a conserved residue. The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing; it was present once in the gnomAD database (1 of 137,447 individuals). The deceased father of the mother died of end-stage kidney disease at age 85; DNA was not available. In vitro functional expression studies showed that the R208H variant was unable to rescue defective glycosylation and maturation of PKD1 (601313), whereas wildtype ALG5 was able to rescue the phenotype.
In 2 distantly related Irish families (F350 and F200) with a late-onset autosomal dominant polycystic kidney disease-like phenotype and tubulointerstitial fibrosis (PKD7; 620056), Elhassan et al. (2024) identified 23 individuals with a heterozygous c.235C-T transition (c.235C-T, NM_013338.5) in the ALG5 gene, resulting in an arg79-to-trp (R79W) substitution. Among these 23 individuals, 18 were clinically affected with a slowly progressive chronic kidney disease. The authors identified abnormal ALG5 distribution in the Golgi apparatus of renal tubular cells. Abnormal accumulation of uromodulin was noted in the endoplasmic reticulum, and decreased plasma and urinary uromodulin levels were also seen in affected persons, suggesting abnormal maturation and trafficking of uromodulin, resulting in structural and functional changes in the kidney.
Elhassan, E. A. E., Kmochova, T., Benson, K. A., Fennelly, N. K., Baresova, V., Kidd, K., Doyle, B., Dorman, A., Morrin, M. M., Kyne, N. C., Vyletal, P., Hartmannova, H., and 23 others. A novel monoallelic ALG5 variant causing late-onset ADPKD and tubulointerstitial fibrosis. Kidney Int. Rep. 9: 2209-2226, 2024. [PubMed: 39081747] [Full Text: https://doi.org/10.1016/j.ekir.2024.04.031]
Gross, M. B. Personal Communication. Baltimore, Md. 3/24/2014.
Imbach, T., Burda, P., Kuhnert, P., Wevers, R. A., Aebi, M., Berger, E. G., Hennet, T. A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic. Proc. Nat. Acad. Sci. 96: 6982-6987, 1999. [PubMed: 10359825] [Full Text: https://doi.org/10.1073/pnas.96.12.6982]
Lemoine, H., Raud, L., Foulquier, F., Sayer, J. A., Lambert, B., Olinger, E., Lefevre, S., Knebelmann, B., Harris, P. C., Trouve, P., Despres, A., Duneau, G., and 14 others. Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis. Am. J. Hum. Genet. 109: 1484-1499, 2022. [PubMed: 35896117] [Full Text: https://doi.org/10.1016/j.ajhg.2022.06.013]