Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13 in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome)

Abstract

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken syndrome) is the prototype of a class of genetic multisystem disorders characterized by defective glycosylation of glycoconjugates^1–4. It is mostly a severe disorder which presents neonatally. There is a severe encephalopathy with axial hypotonia, abnormal eye movements and pronounced psychomotor retardation, as well as a peripheral neuropathy, cerebellar hypoplasia and retinitis pigmentosa. The patients show a peculiar distribution of subcutaneous fat, nipple retraction and hypogonadism. There is a 20% lethality in the first years of life due to severe infections, liver insufficiency or cardiomyopathy^2,3,5. CDG1 shows an autosomal recessive mode of inheritance and has been mapped to chromosome 16p^6,7. Most patients show a deficiency of phosphomannomutase (PMM)⁸, an enzyme necessary for the synthesis of GDP-mannose. We have cloned the PMM1 gene, which is on chromosome 22q13 (ref. 9). We now report the identification of a second human PMM gene, PMM2, which is located on 16p13 and which encodes a protein with 66% identity to PMM1. We found eleven different missense mutations in PMM2 in 16 CDG1 patients from different geographical origins and with a documented phosphomannomutase deficiency. Our results give conclusive support to the biochemical finding that the phosphomannomutase deficiency is the basis for CDG1.