Detailed mapping of the phosphomannomutase 2 (PMM2) gene and mutation detection enable improved analysis for Scandinavian CDG type I families

Abstract

The gene for carbohydrate-deficient glycoprotein syndrome type I (CDG1) has previously been localised by us close to marker D16S406 in chromosome region 16p13.2-3. We also presented data indicating a strong founder mutation associated with a specific haplotype in CDG I patients from western Scandinavia. The phosphomannomutase 2 (PMM2) gene was recently put forward as a likely CDG1 candidate gene. We have now shown that the specific haplotype is associated with the PMM2 mutation 357C > A. Using data from radiation hybrid panel we have refined the position of the PMM2 gene to very close to marker D16S3020 in the interval between D16S406 and AFM282ze1 on the distal side and D16S3087 on the proximal side. Due to the severity of the disease many families request prenatal diagnostic services for CDG I. In the meantime, until the mutation spectrum is fully examined, we propose the combined use of mutation analysis and linkage analysis with polymorphic markers as diagnostic tools for Scandinavian CDG I families requesting prenatal diagnosis. Using this strategy we have to date successfully performed 15 prenatal diagnoses for CDG I.

Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia)

“…The entire group was also analysed for the presence of the second most frequent mutation, F119L, which is particularly prevalent in Scandinavia. 5,6,12 No carriers were identified in either set, indicating a much lower frequency of this mutation. On the basis of the disease frequency and allele distribution (see below), an estimated 1/500 to 1/1000 was expected.…”

“…4,8 The most intriguing observation is the total lack of patients homozygous for the most frequent mutation, R141H, present in more than 75% of patients of Caucasian origin. 4,5 On the other hand, patients homozygous for the other relatively frequent mutation, F119L, have been found, 4,6,9 (see also M Schwartz 1999, unpublished data) as well as one patient homozygous for the rare D65Y mutation. 4 These observations suggested that the R141H mutation is a severe mutation, and that homozygosity may not be compatible with life.…”

“…[3][4][5] The majority of the 30 different mutations detected so far have been of the missense type. [3][4][5][6][7] Probably, only such mutations that retain residual enzymatic activity are tolerated in patients. Extensive allelic heterogeneity has hampered the study of genotype-phenotype correlation.…”

Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli

“…[2][3][4] All but one of the 30 different mutations detected so far have been of the missense type. [2][3][4][5][6] Whilst most patients are compound heterozygotes, homozygosity for the F119L mutation has been observed in a few instances, and one patient is known to be homozygous for D65Y. 3,5,7 In contrast, patients homozygous for the R141H mutation, present in more than 75% of patients of Caucasian origin, have been conspicuously absent in results of the genotype analyses.…”

“…[2][3][4][5][6] Whilst most patients are compound heterozygotes, homozygosity for the F119L mutation has been observed in a few instances, and one patient is known to be homozygous for D65Y. 3,5,7 In contrast, patients homozygous for the R141H mutation, present in more than 75% of patients of Caucasian origin, have been conspicuously absent in results of the genotype analyses. 3,4 These observations suggest that homozygosity for R141H may not be compatible with life.…”