Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate‐deficient glycoprotein syndrome type 1

Abstract

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1) (MIM: 212065) is an autosomal recessive disorder with psychomotor retardation, strokelike episodes, ataxia, and olivopontocerebellar atrophy (OPCA) of neonatal onset. Recently, DNA substitutions in a gene for phosphomannomutase 2 (PMM2), mapped to 16p13, were identified in patients with CDG1. Biochemical findings in previously reported Japanese patients with CDG1 were slightly different from those of Caucasians, suggesting genetic heterogeneity of CDG1 in Japanese patients. We investigated the DNA sequence of PMM2 in two unrelated Japanese families with CDG1. Missense mutations in exon 5 (Phe144Leu) and exon 8 (Tyr229Ser, Arg238Pro) of the PMM2 gene were present in two families, but they were not present in 72 unrelated healthy Japanese individuals. One of the missense mutations, Phe144Leu in exon 5, was common to two families with CDG1. Our findings confirm that mutations in the PMM2 gene account for at least some Japanese patients with CDG1 similar to that seen in Caucasians and that exons 5 and 8 are hot spots of mutations of CDG1 caused by the PMM2 gene.

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

“…On the other hand, R141H has not been found in Japanese patients (Table 1). 4,7 Because the CDG-Ia mutations are genetically lethal, they should slowly disappear unless the loss of alleles is compensated by new mutations or by a heterozygous advantage. The former is not the case because we have clearly shown that the R141H allele has the same genetic background in almost all the patients and the explanation must therefore be a heterozygous advantage for this mutation.…”

“…[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.…”

Characterization of the 415G>A (E139K) PMM2 mutation in carbohydrate-deficient glycoprotein syndrome type Ia disrupting a splicing enhancer resulting in exon 5 skipping

“…CDG type Ia (CDGS1A; MIM# 212065), the most common form with over 250 patients reported worldwide, is an autosomal recessive disorder characterized by a phosphomannomutase (PMM) deficiency and mutations in the PMM2 gene (MIM# 601785) on chromosome 16p13 (Matthijs et al 1997, Matthijs et al 1998. A total of 26 different missense mutations and a single base-pair deletion have so far been described, most of them being located in exons 5 and 8 (Matthijs et al 1998, Kjaergaard et al 1998, Kondo et. al 1999.…”

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.…”