MUTATIONS IN PMM2, A PHOSPHOMANNOMUTASE GENE ON CHROMOSOME 16P13, IN CARBOHYDRATE-DEFICIENT GLYCOPROTEIN TYPE-I SYNDROME (JAEKEN-SYNDROME)

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken sy ndrome) is the prototype of a class of genetic multisystem disorders c haracterized 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 prono unced psychomotor retardation, as well as a peripheral neuropathy, cer ebellar hypoplasia and retinitis pigmentosa. The patients show a pecul iar distribution of subcutaneous fat, nipple retraction and hypogonadi sm. There is a 20% lethality in the first years of life due to severe infections, liver insufficiency or cardiomyopathy(2,3,5). CDG1 shows a n autosomal recessive mode of inheritance and has been mapped to chrom osome 16p(6,7). Most patients show a deficiency of phosphomannomutase (PMM)(8), an enzyme necessary for the synthesis of GDP-mannose. We hav e 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 l ocated on 16p13 and which encodes a protein with 66% identity to PMM1. We found eleven different missense mutations in PMM2 in 16 CDG1 patie nts from different geographical origins and with a documented phosphom annomutase deficiency. Our results give conclusive support to the bioc hemical finding that the phosphomannomutase deficiency is the basis fo r CDG1.