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The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations.

ABSTRACT: PMM2-CDG is an autosomal recessive disorder and the most frequent form of congenital disorder of N-glycosylation, with more than 100 mutations identified to date. Sixty-six patients from 58 unrelated families were diagnosed as PMM2-CDG (CDG-Ia) based on clinical signs or because of a previous affected sibling. They all presented a type 1 serum transferrin isoform pattern, and, in most cases, the disease was confirmed by determining PMM2 activity in fibroblasts and/or lymphocytes. Residual PMM2 activity in fibroblasts ranged from not detectable to 60% of the mean controls. DNA and RNA were isolated from fresh blood or fibroblasts from patients to perform molecular studies of the PMM2 gene, resulting in the identification of 30 different mutations, four of them newly reported here (p.Y102C, p.T118S, p.P184T, and p.D209G). From these 30 mutations, 15 have only been identified among Iberian PMM2-CDG patients. As in other Caucasian populations, p.R141H was the most frequent mutation (24 alleles, prevalence 20.6%), but less than in other European series in which this mutation represents 35-43% of the disease alleles. The next frequent mutations were p.D65Y (12 alleles, prevalence 10.3%) and p.T237M (9 alleles, prevalence 7.6%), while p.F119L and p.E139K, the most frequent changes in Scandinavian and French populations, respectively, were not found in our patients. The most common genotype was [p.R141H]?+?[p.T237M], and four homozygous patients for p.Y64C, p.D65Y, p.P113L, and p.T237M were detected. The broad mutational spectrum and the diversity of phenotypes found in the Iberian populations hamper genotype-phenotype correlation.

SUBMITTER: Perez B

PROVIDER: S-EPMC3509825 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations.

Pérez B B Briones P P Quelhas D D Artuch R R Vega A I AI Quintana E E Gort L L Ecay M J MJ Matthijs G G Ugarte M M Pérez-Cerdá C C

JIMD reports 20110622

PMM2-CDG is an autosomal recessive disorder and the most frequent form of congenital disorder of N-glycosylation, with more than 100 mutations identified to date. Sixty-six patients from 58 unrelated families were diagnosed as PMM2-CDG (CDG-Ia) based on clinical signs or because of a previous affected sibling. They all presented a type 1 serum transferrin isoform pattern, and, in most cases, the disease was confirmed by determining PMM2 activity in fibroblasts and/or lymphocytes. Residual PMM2 a ...[more]

PMID: 23430838

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Project description:The Iberian Peninsula has been the focus of attention of numerous studies dealing with mitochondrial DNA (mtDNA) variation, most of them targeting the control region segment. In the present study we sequenced the control region of 3,024 Spanish individuals from areas where available data were still limited. We also compiled mtDNA haplotypes from the literature involving 4,588 sequences and 28 population groups or small regions. We meta-analyzed all these data in order to shed further light on patterns of geographic variation, taking advantage of the large sample size and geographic coverage, in contrast with the atomized sampling strategy of previous work. The results indicate that the main mtDNA haplogroups show primarily clinal geographic patterns across the Iberian geography, roughly along a North-South axis. Haplogroup HV0 (where haplogroup U is nested) is more prevalent in the Franco Cantabrian region, in good agreement with previous findings that identified this area as a climate refuge during the Last Glacial Maximum (LGM), prior to a subsequent demographic re-expansion towards Central Europe and the Mediterranean. Typical sub-Saharan and North African lineages are slightly more prevalent in South Iberia, although at low frequencies; this pattern has been shaped mainly by the transatlantic slave trade and the Arab invasion of the Iberian Peninsula. The results also indicate that summary statistics that aim to measure molecular variation, or AMOVA, have limited sensitivity to detect population substructure, in contrast to patterns revealed by phylogeographic analysis. Overall, the results suggest that mtDNA variation in Iberia is substantially stratified. These patterns might be relevant in biomedical studies given that stratification is a common cause of false positives in case-control mtDNA association studies, and should be also considered when weighting the DNA evidence in forensic casework, which is strongly dependent on haplotype frequencies.

Dataset Information

The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations.

Publications

The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations.

Similar Datasets

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