Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry

Congenital disorders of glycosylation (CDG) are caused by autosomal recessi ve mutations in genes affecting-N-glycan biosynthesis. Mutations in the PMM 2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <- ---> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnor malities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in ad dition to feeding problems. However, the clinical symptoms vary greatly, Th e great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explai ned by lack of global awareness of the disorder. Here we report an Asian pa tient with prominent systemic features that we diagnosed with CDG-Ia result ing from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to resul t in lower mRNA levels, and the L104V has been functionally analyzed in a y east expression system together with known mutations, The Filipino and Camb odian origins of the parents show that CDG-Ia mutations occur in these ethn ic groups as well as in Caucasians. (C) 2001 Academic Press.