LACK OF HOMOZYGOTES FOR THE MOST FREQUENT DISEASE ALLELE IN CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME TYPE 1A

Carbohydrate-deficient-glycoprotein syndrome type 1 (CDG1; also known as ''Jaeken syndrome'') is an autosomal recessive disorder characteriz ed by defective glycosylation. Most patients show a deficiency of phos phomannomutase (PMM), the enzyme that converts mannose 6-phosphate to mannose 1-phosphate in the synthesis of GDP-mannose. The disease is li nked to chromosome 16p13, and mutations have recently seen identified in the PMM2 gene in CDG1 patients with a PMM deficiency (CDG1A). The a vailability of the genomic sequences of PMM2 allowed us to screen for mutations in 56 CDG1 patients from different geographic origins, By SS CP analysis and by sequencing, we identified 23 different missense mut ations and 1 single-base-pair deletion. In total, mutations were found on 99% of the disease chromosomes in CDG1A patients, The R141H substi tution is present on 43 of the 112 disease alleles. However, this muta tion was never observed in the homozygous state, suggesting that-homoz ygous for these alterations is incompatible with life. On the other ha nd, patients were found homozygous for the D65Y and F119L mutations, w hich must therefore be mild mutations. One particular genotype, R141H/ D188G, which is prevalent in Belgium and the Netherlands, is associate d with a severe phenotype and a high mortality, Apart from this, there is only a limited relation between the genotype and the clinical phen otype.