The ALG9 gene encodes a protein called alpha-1,2-mannosyltransferase that functions in lipid-linked oligosaccharide assembly. Specifically, this protein catalyzes two steps in the N-linked pathway of lipid-linked oligosaccharide biosynthesis. The N-linked pathway is a complex multi enzymatic process that involves two major steps. The first of these steps takes place on the cytosolic side of the ER with the production of a dolichol pyrophosphate-linked heptasaccharide. This metabolite is then translocated to the luminal side of the ER where four mannose residues and three glucose residues are added to the lipid-linked precursor oligosaccharide. The ALG9 protein catalyzes the addition of two different mannose residues, the seventh mannose residue on the B-arm as well as the ninth mannose residue on the C-arm to the lipid-linked oligosaccharide.
Mutations in the ALG9 gene are associated with two different kinds of disorders. Congenital disorder of glycosylation, type Il is a disorder that results in progressive microcephaly, hypotonia, developmental delay, drug-resistant infantile epilepsy, and hepatomegaly. The other disorder linked to this gene is Gillessen-Kaesbach–Nishimura skeletal dysplasia, a rare lethal autosomal recessive syndrome with skeletal dysplasia and visceral abnormalities. In addition, variants involving the ALG9 gene have been shown to be associated with a high frequency of bipolar affective disorder in some families.
The ALG9 gene is located in 11q23. It is made up of 15 exons and is about 85 kb long. The gene is expressed in all anatomical regions of the central nervous system. Exon 11 can be spliced at two sites, resulting in four major protein isoforms. The protein product encoded by the gene is made up of 611 amino acids.
AlSubhi et al. (2016) studied four patients from a large multiply consanguineous family diagnosed with ALG9-CDG. Mendeliome assay revealed a previously reported homozygous missense mutation, (c.1588G>A, p.E530K) in the ALG9 gene in the patients, which was confirmed by Sanger sequencing. All parents were tested and found to be heterozygous for the mutation.