Alternative titles; symbols
HGNC Approved Gene Symbol: ALG9
SNOMEDCT: 720978005;
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38): 11:111,768,025-111,871,581 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.1 | Congenital disorder of glycosylation, type Il | 608776 | Autosomal recessive | 3 |
| Gillessen-Kaesbach-Nishimura syndrome | 263210 | Autosomal recessive | 3 |
The ALG9 gene encodes an alpha-1,2-mannosyltransferase that catalyzes 2 steps in the lipid-linked precursor oligosaccharide (LLO) in the N-linked pathway of glycosylation (summary by Tham et al., 2016).
Baysal et al. (2002) identified the DIBD1 gene while investigating the breakpoint junctions of a balanced chromosomal translocation, t(9;11)(p24;q23), that was identified in 6 members of a family with bipolar affective disorder (BPAD; see 125480) or recurrent unipolar depression (Baysal et al., 2002; Smith et al., 1989). The predicted 611-amino acid DIBD1 protein is a mannosyltransferase similar to the S. cerevisiae Alg9 protein of the N-glycosylation pathway and contains 8 transmembrane helices. Northern blot analysis detected expression of DIBD1 in all tissues tested, with highest expression in heart, liver, and pancreas. The most abundant transcript was 2.5 kb, although 0.25-, 5.5-, and 7.0-kb transcripts were also observed. In subregions of the brain, the 2.5- and 7.0-kb transcripts were expressed ubiquitously.
By genomic sequence analysis, Baysal et al. (2002) determined that the ALG9 gene has 15 exons and spans 85 kb.
By genomic sequence analysis, Baysal et al. (2002) mapped the ALG9 gene to chromosome 11q23.
Using an intragenic polymorphism and other markers, Baysal et al. (2002) performed linkage and linkage disequilibrium analyses in 2 National Institute of Mental Health bipolar pedigree series and found no support for a role of DIBD1 in disease susceptibility.
Congenital Disorder of Glycosylation Type Il
Frank et al. (2004) reported a female patient with a novel type of CDG I (CDG1L; 608776). The authors detected a homozygous missense mutation (E523K; 606941.0001) in the ALG9 gene. A yeast complementation assay lacking the ALG9 gene confirmed the deleterious effect of the E523K mutation as well as the functional homology between the human and Saccharomyces cerevisiae ALG9.
Weinstein et al. (2005) reported a female infant with CDG Il in whom they identified homozygosity for a missense mutation in the ALG9 gene (Y286C; 606941.0002).
In 4 affected members of a large consanguineous Saudi Arabian family with CDG1L, AlSubhi et al. (2016) identified a homozygous missense mutation in the ALG9 gene (E359K; 606941.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but patient cells showed hypoglycosylation of serum transferrin, consistent with CDG type I.
In 2 unrelated patients with CDG1L, Himmelreich et al. (2022) identified the same homozygous missense mutation in the ALG9 gene (L487P; 606941.0005). In patient 1 the mutation was identified by Sanger sequencing of the ALG9 gene, and in patient 2 it was identified by sequencing of a panel of genes underlying congenital disorders of glycosylation. ALG9 protein expression was reduced in fibroblasts from patient 1 compared to controls. Treatment of the fibroblasts with cycloheximide, followed by Western blot analysis, demonstrated that the reduced expression in patient cells was due to protein instability.
Gillessen-Kaesbach-Nishimura Syndrome
In a stillborn girl and 2 fetuses from 2 unrelated consanguineous families with Gillessen-Kaesbach-Nishimura syndrome (GIKANIS; 263210), Tham et al. (2016) identified a homozygous truncating mutation in the ALG9 gene (606941.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis suggested a founder effect. The 2 fetuses from the second family were also homozygous for a rare missense variant (D968H) affecting a highly conserved residue in the ANK3 gene (600465); mutation in the ANK3 gene is associated with autosomal recessive mental retardation-37 (MRT37; 615493). The parents were heterozygous carriers of the ANK3 variant. Tham et al. (2016) suggested that the more severe phenotype in these patients compared to those with CDG1L resulted from the truncating mutation, which was predicted to result in a complete loss of function.
Frank et al. (2004) described a novel type of congenital disorder of glycosylation (CDG1L; 608776) in a female infant born at term as a twin with a birth weight of 2.75 kg, length of 44 cm, and head circumference of 31.5 cm. As she grew older, her clinical features included severe microcephaly, central hypotonia, seizures, hepatomegaly, developmental delay, and bronchial asthma. This pattern of clinical presentation was compatible with CDG, a diagnosis confirmed by isoelectric focusing analysis of serum transferrin. The patient's sample showed an increase of disialo- and asialo-transferrin, indicative of CDG I. Normal values of phosphomannomutase activity excluded the most frequent form of CDG, type Ia (212065). The accumulation of 2 lipid-linked oligosaccharides (LLOs) suggested a possible defect at the level of alpha-1,2-mannosyltransferase, which, in yeast, catalyzes the addition of the seventh and ninth mannose residues on growing LLOs. In the patient, ALG9 cDNA was found to carry the point mutation 1567G-A, which caused the amino acid change glu523-to-lys (E523K) in the ALG9 protein. The mutation was also detected at the genomic level by sequencing exon 14 of the patient's ALG9 gene.
In a female infant with congenital disorder of glycosylation type Il (CDG1L; 608776), Weinstein et al. (2005) identified homozygosity for an 860A-G transition in the ALG9 gene, resulting in a tyr286-to-cys (Y286C) substitution. The parents were heterozygous for the mutation.
In a stillborn girl and 2 fetuses from 2 unrelated consanguineous families with Gillessen-Kaesbach-Nishimura syndrome (GIKANIS; 263210), Tham et al. (2016) identified a homozygous T-to-A transversion (c.1173+2T-A, NM_024740.2) in the splice donor site of exon 10 of the ALG9 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and was not found in the ExAC database or in 249 control exomes. Analysis of patient cells showed that the mutation caused the skipping of exon 10, resulting in a frameshift and premature termination (Val340AlafsTer57). Haplotype analysis around the ALG9 gene in the 2 families suggested a founder effect. In addition to a skeletal dysplasia and polycystic kidney disease, spleen tissue showed a transferrin (190000) glycosylation defect. The 2 fetuses from the second family were also homozygous for a rare missense variant (D968H) affecting a highly conserved residue in the ANK3 gene (600465); mutation in the ANK3 gene is associated with autosomal recessive mental retardation-37 (MRT37; 615493). The parents were heterozygous carriers of the ANK3 variant.
In 4 affected members of a large consanguineous Saudi Arabian family with congenital disorder of glycosylation (CDG1L; 608776), AlSubhi et al. (2016) identified a homozygous c.1558G-A transition (c.1075G-A, NM_024740.2) in the ALG9 gene, resulting in a glu530-to-lys (E359K) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but patient cells showed hypoglycosylation of serum transferrin consistent with type I CDG. (In the article by AlSubhi et al. (2016), the mutation is described as c.1558G-A, E530K in the text and Table 1, but as c.1075G-A, E359K in the abstract. AlSubhi (2018) confirmed that the correct mutation is c.1075G-A, E359K.)
In 2 unrelated patients with congenital disorder of glycosylation (CDG1L; 608776), Himmelreich et al. (2022) identified homozygosity for a c.1460T-C transition (c.1460T-C, NM_024740.2) in exon 12 of the ALG9 gene, resulting in a leu487-to-pro (L487P) substitution. In patient 1 the mutation was identified by Sanger sequencing of the ALG9 gene, and in patient 2 the mutation was identified by sequencing of a panel of genes underlying congenital disorders of glycosylation. The mutation was not present in the gnomAD database. ALG9 protein expression was reduced in fibroblasts from patient 1 compared to controls.
AlSubhi, S., AlHashem, A., AlAzami, A., Tlili, K., AlShahwan, S., Lefeber, D., Alkuraya, F. S., Tabarki, B. Further delineation of the ALG9-CDG phenotype. JIMD Rep. 27: 107-112, 2016. [PubMed: 26453364] [Full Text: https://doi.org/10.1007/8904_2015_504]
AlSubhi, S. Personal Communication. Riyadh, Saudi Arabia 2/1/2018.
Baysal, B. E., Potkin, S. G., Farr, J. E., Higgins, M. J., Korcz, J., Gollin, S. M., James, M. R., Evans, G. A., Richard, C. W., III. Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree. Am. J. Med. Genet. 81: 81-91, 1998. [PubMed: 9514593]
Baysal, B. E., Willett-Brozick, J. E., Badner, J. A., Corona, W., Ferrell, R. E., Nimgaonkar, V. L., Detera-Wadleigh, S. D. A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family. Neurogenetics 4: 43-53, 2002. [PubMed: 12030331] [Full Text: https://doi.org/10.1007/s10048-001-0129-x]
Frank, C. G., Grubenmann, C. E., Eyaid, W., Berger, E. G., Aebi, M., Hennet, T. Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL. Am. J. Hum. Genet. 75: 146-150, 2004. [PubMed: 15148656] [Full Text: https://doi.org/10.1086/422367]
Himmelreich, N., Dimitrov, B., Zielonka, M., Hullen, A., Hoffmann, G. F., Juenger, H., Muller, H., Lorenz, I., Busse, B., Marschall, C., Schluter, G., Thiel, C. Missense variant c.1460 T-C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature. Molec. Genet. Metab. 136: 274-281, 2022. [PubMed: 35839600] [Full Text: https://doi.org/10.1016/j.ymgme.2022.06.005]
Smith, M., Wasmuth, J., McPherson, J. D., Wagner, C., Grandy, D., Civelli, O., Potkin, S., Litt, M. Cosegregation of an 11q22.3-9p22 translocation with affective disorder: proximity of the dopamine D2 receptor gene relative to the translocation breakpoint. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A220 only, 1989.
Tham, E., Eklund, E. A., Hammarsjo, A., Bengtson, P., Geiberger, S., Lagerstedt-Robinson, K., Malmgren, H., Nilsson, D., Grigelionis, G., Conner, P., Lindgren, P., Lindstrand, A., Wedell, A., Albage, M., Zielinska, K., Nordgren, A., Papadogiannakis, N., Nishimura, G., Grigelioniene, G. A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9. Europ. J. Hum. Genet. 24: 198-207, 2016. [PubMed: 25966638] [Full Text: https://doi.org/10.1038/ejhg.2015.91]
Weinstein, M., Schollen, E., Matthijs, G., Neupert, C., Hennet, T., Grubenmann, C. E., Frank, C. G., Aebi, M., Clarke, J. T. R., Griffiths, A., Seargeant, L., Poplawski, N. CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features. Am. J. Med. Genet. 136A: 194-197, 2005. [PubMed: 15945070] [Full Text: https://doi.org/10.1002/ajmg.a.30851]