Alternative titles; symbols
HGNC Approved Gene Symbol: ALG8
SNOMEDCT: 720977000;
Cytogenetic location: 11q14.1 Genomic coordinates (GRCh38) : 11:78,100,946-78,139,626 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q14.1 | Congenital disorder of glycosylation, type Ih | 608104 | Autosomal recessive | 3 |
| Polycystic liver disease 3 with or without kidney cysts | 617874 | Autosomal dominant | 3 |
The alpha-3-glucosyltransferase ALG8 adds the second glucose to the lipid-linked oligosaccharide precursor used in the N-glycosylation of proteins.
By searching an EST database for human homologs of yeast genes, Stanchi et al. (2001) identified ALG8. They obtained the full-length cDNA and determined that the ALG8 protein contains 532 amino acids. It shares 38% amino acid identity with yeast ALG8.
By database analysis, Oriol et al. (2002) identified ALG8. They determined that the 526-amino acid protein has 12 transmembrane domains and an endoplasmic reticulum retention signal (KTKKQ).
Chantret et al. (2003) determined that the ALG8 gene contains 13 exons.
By radiation hybrid analysis, Stanchi et al. (2001) mapped the ALG8 gene to chromosome 11pter-p15.5. However, Chantret et al. (2003) mapped the ALG8 gene to chromosome 11q14 by genomic sequence analysis.
Congenital Disorder of Glycosylation Ih
In a patient with congenital disorder of glycosylation Ih (CDG1H; 608104), Chantret et al. (2003) identified compound heterozygosity for 2 frameshift mutations (608103.0001-608103.0002) in exon 4 of the ALG8 gene.
Schollen et al. (2004) described 3 patients from 2 families with CDH1H associated with a severe clinical phenotype and early infant death. In each family they identified compound heterozygosity for a splice site mutation and a missense mutation (see 608103.0003-608103.0005). Each parent was a carrier of one of the respective mutations.
Hock et al. (2015) identified compound heterozygous mutations in the ALG8 gene (608103.0004; 608103.0007; 608103.0010) in 2 unrelated patients (patients 2 and 5) with CDG1H. The mutations were identified by sequencing of the ALG8 gene. Patient 2 had a similarly affected deceased sib who did not undergo gene sequencing. All 3 patients had a type 1 pattern on plasma transferrin isoelectric focusing.
Polycystic Liver Disease 3 with or without Polycystic Kidney Disease
In 5 unrelated patients with polycystic liver disease-3 with or without kidney cysts (PCLD3; 617874), Besse et al. (2017) identified heterozygous truncating mutations in the ALG8 gene (608103.0007-608103.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present at low frequencies in the ExAC database. One patient (W-YU363) had an affected daughter who also carried the mutation. Otherwise, family members were not available for segregation analysis. Statistical analysis of the frequency of loss-of-function ALG8 variants among patients compared to controls suggested that ALG8 is a candidate gene for the disorder. Functional studies of the variants and studies of patient cells were not performed, but CRISPR/Cas9 inactivation of both Alg8 alleles in a mouse epithelial cell line resulted in decreased levels of the Pkd1 (601313) protein, decreased posttranslational glycosylation and modification of Pkd1, and impaired trafficking of Pkd1 to the cell surface and, by extension, to cilia. Reexpression of wildtype Alg8 rescued these defects. These findings suggested that defective biogenesis of PKD1 in the endoplasmic reticulum and impaired PKD1 function and signaling mechanistically underlies the development of cysts. The patients were ascertained from a cohort of 102 patients with polycystic liver disease who did not have mutations in the PRKCSH (177060) or SEC63 (608648) genes and who underwent whole-exome sequencing.
In a patient with congenital disorder of glycosylation Ih (CDG1H; 608104), Chantret et al. (2003) identified compound heterozygosity for 2 mutations in exon 4 of the ALG8 gene, a 1-bp deletion (413delC) inherited from the father and a 1-bp insertion (396insA; 608103.0002) inherited from the mother. Both mutations gave rise to premature stop codons predicted to generate severely truncated proteins. Because the translation inhibitor emetine stabilized the ALG8 mRNA from the patient to normal levels, it was considered likely that both transcripts underwent nonsense-mediated mRNA decay. The cells from the patient were successfully complemented with wildtype ALG8 cDNA.
For discussion of the 1-bp insertion in the ALG8 gene (396insA) that was found in compound heterozygous state in a patient with congenital disorder of glycosylation Ih (CDG1H; 608104) by Chantret et al. (2003), see 608103.0001.
In a brother and sister with congenital disorder of glycosylation Ih (CDG1H; 608104), Schollen et al. (2004) identified compound heterozygosity for an A-to-G transition at position -2 of intron 1 and a 139A-C transversion in exon 2. The splice site mutation causes use of a cryptic splice site, resulting in an 11-bp deletion and a premature stop at codon 38; the transversion in exon 2 results in a thr47-to-pro substitution (T47P; 608103.0004). The sibs also carried a 665A-G polymorphism, which results in an asn222-to-ser (N222S) substitution, on the same allele as the missense mutation. The authors noted that these patients had a much more severe presentation than the patient described by Chantret et al. (2003), including antenatal symptoms and early infant death.
For discussion of the thr47-to-pro (T47P) mutation in the ALG8 gene that was found in compound heterozygous state in sibs with congenital disorder of glycosylation Ih (CDG1H; 608104) by Schollen et al. (2004), see 608103.0003.
In 2 unrelated patients with CDG1H, Hock et al. (2015) identified compound heterozygous mutations in the ALG8 gene. Both patients carried the c.139A-C transversion, resulting in a T47P substitution, on one allele. Patient 2, from the Tyrolean region of Austria, carried a c.1090C-T transition in exon 10 on the other allele, resulting in an arg364-to-ter (R364X; 608103.0007) substitution, and patient 5 carried a 2-bp deletion (c.1219_1220delCT; 608103.0010) in exon 11 on the other allele, predicted to result in a frameshift and premature termination (Leu407AspfsTer23). The mutations were identified by sequencing of the ALG8 gene. Patient 2 had a similarly affected deceased older sib who had not undergone genetic testing.
In a male infant with congenital disorder of glycosylation Ih (CDG1H; 608104), Schollen et al. (2004) identified compound heterozygosity for an A-to-G transition at position +4 of intron 6 and an 824G-A transition in exon 8, resulting in a gly275-to-asp substitution (G275D; 608103.0006). The patient had multiple dysmorphic features of the head and extremities, bilateral thoracic and pulmonary hypoplasia, cardiac defects, and diffuse renal and hepatic cystic disease as well as hematopoietic abnormalities, and died at 3 months of age after developing dyspnea due to progressive ascites.
For discussion of the gly275-to-asp (G275D) mutation in the ALG8 gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation Ih (CDG1H; 608104) by Schollen et al. (2004), see 608103.0005.
Polycystic Liver Disease 3 with Kidney Cysts
In 3 unrelated patients (YU313, T-55, and T-70) with polycystic liver disease-3 with kidney cysts (PCLD3; 617874), Besse et al. (2017) identified a heterozygous c.1090C-T transition in the ALG8 gene, resulting in an arg364-to-ter (R364X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (4.5 x 10(-5)) in the ExAC database. Two patients were of European descent and 1 was of African American descent. No family data were available for segregation analysis. Functional studies of the variant and studies of patient cells were not performed.
Congenital Disorder of Glycosylation, Type Ih
For discussion of the c.1090C-T transition in the ALG8 gene, resulting in an R364X substitution, that was found in compound heterozygous state in a patient (patient 2) with congenital disorder of glycosylation type Ih (CDG1H; 608104) by Hock et al. (2015), see 608103.0004.
In a 59-year-old woman of Finnish descent (FINN59) with polycystic liver disease-3 without kidney cysts (PCLD3; 617874), Besse et al. (2017) identified a heterozygous G-to-T transversion (c.1038+1G-T) in intron 10 of the ALG8 gene, resulting in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (1.65 x 10(-4)) in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In a 63-year-old man of European descent (W-YU363) with polycystic liver disease-3 with kidney cysts (PCLD3; 617874), Besse et al. (2017) identified a heterozygous c.535C-T transition in the ALG8 gene, resulting in an arg179-to-ter (R179X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (1.705 x 10(-5)) in the ExAC database. His 19-year-old daughter (W-YU364) also carried the mutation; she had 8 kidney cysts, but no liver cysts. Functional studies of the variant and studies of patient cells were not performed.
For discussion of the 2-bp deletion (c.1219_1220delCT) in the ALG8 gene, predicted to result in a frameshift and premature termination (Leu407AspfsTer23), that was found in compound heterozygous state in a patient (patient 5) with congenital disorder of glycosylation Ih (CDG1H; 608104) by Hock et al. (2015), see 608103.0004.
Besse, W., Dong, K., Choi, J., Punia, S., Fedeles, S. V., Choi, M., Gallagher, A.-R., Huang, E. B., Gulati, A., Knight, J., Mane, S., Tahvanainen, E., Tahvanainen, P., Sanna-Cherchi, S., Lifton, R. P., Watnick, T., Pei, Y. P., Torres, V. E., Somlo, S. Isolated polycystic liver disease genes define effectors of polycystin-1 function. J. Clin. Invest. 127: 1772-1785, 2017. Note: Erratum: J. Clin. Invest. 127: 3558 only, 2017. [PubMed: 28375157] [Full Text: https://doi.org/10.1172/JCI90129]
Chantret, I., Dancourt, J., Dupre, T., Delenda, C., Bucher, S., Vuillaumier-Barrot, S., de Baulny, H. O., Peletan, C., Danos, O., Seta, N., Durand, G., Oriol, R., Codogno, P., Moore, S. E. H. A deficiency in dolichyl-P-glucose:Glc-1-Man-9-GlcNAc-2-PP-dolichyl alpha-3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J. Biol. Chem. 278: 9962-9971, 2003. [PubMed: 12480927] [Full Text: https://doi.org/10.1074/jbc.M211950200]
Hock, M., Wegleiter, K., Raiser, E., Kiechl-Kohlendorfer, U., Scholl-Burgi, S., Fauth, C., Steichen, E., Pichler, K., Lefeber, D. J., Matthjis, G., Keldermans, L., Mauer, K., Zschocke, J., Karall, D. ALG8-CDG: novel patient and review of the literature. Orphanet J. Rare Dis. 10: 73, 2015. [PubMed: 26066342] [Full Text: https://doi.org/10.1186/s13023-015-0289-7]
Oriol, R., Martinez-Duncker, I., Chantret, I., Mollicone, R., Codogno, P. Common origin and evolution of glycosyltransferases using Dol-P-monosaccharides as donor substrate. Molec. Biol. Evol. 19: 1451-1463, 2002. [PubMed: 12200473] [Full Text: https://doi.org/10.1093/oxfordjournals.molbev.a004208]
Schollen, E., Frank, C. G., Keldermans, L., Reyntjens, R., Grubenmann, C. E., Clayton, P. T., Winchester, B. G., Smeitink, J., Wevers, R. A., Aebi, M., Hennet, T., Matthijs, G. Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). (Letter) J. Med. Genet. 41: 550-556, 2004. [PubMed: 15235028] [Full Text: https://doi.org/10.1136/jmg.2003.016923]
Stanchi, F., Bertocco, E., Toppo, S., Dioguardi, R., Simionati, B., Cannata, N., Zimbello, R., Lanfranchi, G., Valle, G. Characterization of 16 novel human genes showing high similarity to yeast sequences. Yeast 18: 69-80, 2001. [PubMed: 11124703] [Full Text: https://doi.org/10.1002/1097-0061(200101)18:1<69::AID-YEA647>3.0.CO;2-H]