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POSTER NO: 193 Molecular genetics of Congenital Disorders of Glycosylation type Ia (CDG-Ia): tracing the age of two ancestral mutations to 1500 and _5000 years respectively
1E Schollen, 2R Colombo, 1K Martens, 1G Matthijs The PMM2 gene, which is defective in CDG-Ia, was cloned 3 years ago. We have analysed over a 100 patients, and collated data from 5 other research and diagnostic laboratories. In total, 58 different mutations were found in 249 patients from 23 countries. Three important conclusions arise. First, there is a plethora of missense mutations causing CDG-Ia. The two most common mutations are R141H and F119L, accounting for respectively 37% and 16% of all mutant chromosomes in the Caucasian population. The other mutations are scattered over the gene. The distribution and frequency of both mutations suggest a clear founder effect. To estimate the age and the and origin of the most recent common ancestor (MRCA) of R141H and F119L, we performed haplotype analysis with six polymorfic markers flanking PMM2. A core haplotype of four markers (D16S768; D16S406; D16S3020; D16S3087) was identified in >70% of F119L chromosomes. Therefore F119L must be a relatively recent mutation with an age of 58 to 89 generations. The strong linkage disequilibrium between D16S3020 and R141H and the widespread distribution of R141H is consistent with an old mutation (age >250 generations). Second, the lack of PMM2 activity is incompatible with life. This conclusion stems from the observation that there is a total lack of patients homozygous for the very frequent R141H mutation. The lack of homozygotes for R141H is easily explained by the severity of the mutation: R141H encodes the least active protein. Still, the carrier frequency of the R141H mutation is on the order of 1 in 50 to 1 in 150 in the West-European population. This implicates a heterozygote advantage for R141H (fitness = 1.06). |