Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1

Abstract

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1; McKusick No. 212065) is an autosomal recessively inherited disease characterised clinically by central nervous system dysfunction and biochemically by hypoglycosylation of many serum proteins. Most patients with CDG1 have deficient activity of phosphomannomutase. The locus for this enzyme has been mapped to 16p13, and a gene, PMM2, encoding phosphomannomutase has been isolated. We identified 34 mutations on 36 disease chromosomes in 18 unrelated Danish patients with CDG1. All patients have less than 15% residual activity of phosphomannomutase. Two mutations account for 88% of all mutations: F119L and R141H were each found in 16 out of 36 CDG1 alleles. These two mutations were found to be in linkage disequilibrium with two different alleles of the marker D16S3020, suggesting that there is one ancestral origin for each mutation. Two new mutations, G117R and D223E, were identified also. Surprisingly, no patient was homozygous for either of the two common mutations, suggesting that homozygosity for these mutations is either lethal or so benign that such patients are not detected.

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

“…Figure 3 shows the activities expressed as percent of normal wild type human PMM activity. The plasmid carrying the common mutation R141H 40,41 gave the same activity as the vector without insert. This finding is expected, because this mutation is believed to be lethal in the homozygous state.…”

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

“…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homozygous for the other relatively frequent mutation, F119L, have been found, 4,6,9 (see also M Schwartz 1999, unpublished data) as well as one patient homozygous for the rare D65Y mutation. 4 These observations suggested that the R141H mutation is a severe mutation, and that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 In two independent surveys on patients with CDG-Ia, mutations in the coding region of the PMM2 gene were found on 145 of 148 disease chromosomes (98%). [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.…”

“…[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.…”

Clinical utility gene card for: Phosphomannomutase 2 deficiency

“…No patient homozygous for this mutation has been reported, because this severe mutation is not compatible with life in the homozygous state. [3][4][5] The standard reference sequence indicating reported variants (ENSG00000140650) and a reference for exon numbering (ENST00000268261) can be found at www.ensemble.org.…”