title: Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.
abstract: Congenital Disorder of Glycosylation (CDG) type Ic is caused by mutations in ALG6. This gene encodes an alpha1,3 glucosyltransferase used for synthesis of the lipid linked oligosaccharide (LLO) precursor of the protein N-glycosylation pathway. CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties. We previously identified a typical patient with a heterozygous point mutation, c.391T>C (p.Tyr131His) in ALG6. Using complementation analysis of ALG6-deficient yeast, we show that this alteration is as severe as the most common disease-causing mutation, c998C>T (p. Ala333Val), which occurs in over half of all known CDG-Ic patients. The frequency of c.391T>C (p.Tyr131His) in the US population, is 0.0214, suggesting that homozygotes would occur at a rate of& tilde;1:2,200. We identified one patient with typical CDG-Ic symptoms and a homozygous p.Tyr131His alteration in ALG6. However, in contrast to most CDG patients, her LLO and plasma transferrin glycosylation appeared normal. Thus, it is unclear whether c.391T>C causes CDG-Ic or contributes to the symptoms. Genotyping additional patients with CDG-like symptoms will be required to resolve this issue.
mesh_terms: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D017354:Point Mutation
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C097753:PDCD6 protein, human