Fine Mapping of the Gene for Carbohydrate-Deficient Glycoprotein Syndrome, Type I (CDG1): Linkage Disequilibrium and Founder Effect in Scandinavian Families

Bjursell, Cecilia; Stibler, Helena; Wahlström, Jan; Kristiansson, Bengt; Skovby, Flemming; Strømme, Petter; Blennow, Gösta; Martinsson, Tommy

doi:10.1006/geno.1996.4488

Cited by 51 publications

(53 citation statements)

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“…Large forests in the inland of Sweden also served as a border towards the east as they were not safe to pass through. The genetic specificity and stability of the population of western Sweden has also been reported for other genetic disorders such as carbohydrate deficient glycoprotein syndrome type 1A (CDG1A) 28 and psoriasis. 29 We would have expected the 3171ins5 mutation to have appeared in Denmark since the geographical closeness is apparent (Figure 3), but also for historical reasons, the south-western parts of Sweden belonged to Denmark from the middle ages until the 17th century.…”

Section: Haplotype Construction and Age Estimation Of 3171ins5mentioning

confidence: 99%

The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation

et al. 2001

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The most recurrent BRCA1/BRCA2 mutation in Sweden is the BRCA1 mutation 3171ins5. In the western part of Sweden this mutation accounts for as much as 77% of identified mutations in these two genes. Our aim was to analyse in detail the haplotype and founder effects of the 3171ins5 and furthermore attempt to estimate the time of origin of the mutation. In the study we included eighteen apparently unrelated families with hereditary breast and/or ovarian cancer. At least one individual in each family had previously tested positive for the 3171ins5 mutation. Polymorphic microsatellite markers were used for the haplotype analyses. The markers were located within or flanking the BRCA1 gene spanning a region of 17.3 cM. We found several different haplotypes both for disease alleles and for the normal alleles. However, a conserved haplotype of 3.7 cM was observed in the 3171ins5 carriers spanning over four markers located within or very close to the BRCA1 gene. As this haplotype was not present in any of the normal controls it is highly likely that this is a mutation identical by descent, i.e. a true founder. The results from the haplotype analyses were used to estimate the age of the mutation. Estimations based on the P excess and linkage disequilibrium gives a first appearance of the mutation sometime around the 6th century, approximately 50 generations ago. European Journal of Human Genetics (2001) 9, 787 ± 793.

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Section: Haplotype Construction and Age Estimation Of 3171ins5mentioning

confidence: 99%

The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation

et al. 2001

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“…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.…”

Section: Frequency Of R141h In Two Normal Populationsmentioning

confidence: 99%

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

et al. 2000

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The R141H mutation in the PMM2 gene is the most frequent mutation in type Ia of the congenital disorders of glycosylation (formerly carbohydrate-deficient glycoprotein syndromes)(CDG-Ia). However, it has never been observed in the homozygous state. Homozygosity for this mutation is probably incompatible with life. In this study, we determined the frequency of R141H in two normal populations: in neonates of Dutch origin 1/79 were carriers, whilst in the Danish population, a carrier frequency of 1/60 was found. These figures are clearly in disequilibrium with the frequency of CDG-Ia that has been estimated at 1/80 000 to 1/40 000 in these populations. Haplotype analysis of 43 patients with the R141H mutation of different geographic origins indicated that the R141H is an old mutation in the Caucasian population. Based on the new data, the disease frequency has been calculated at 1/20 000 in these populations. It is concluded that the disease is probably underdiagnosed.

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“…1,2 Biochemical diagnosis relies on isoelectric focusing of serum glycoproteins which shows a cathodal shift of isoforms due to undersialylation. 3 The majority of CDG1 patients have a deficiency of phosphomannomutase which converts mannose-6-P to mannose-1-P. [4][5][6] A locus for CDG1 has been mapped to 16p13, [7][8][9] and overrepresentation of a certain haplotype in CDG1 families from southern Scandinavia suggests the presence of a specific mutation with a founder effect in this area. 9 Recently, two genes, both encoding a phosphomannomutase, have been cloned on the basis of their homology to yeast phosphomannomutase SEC53.…”

Section: Introductionmentioning

confidence: 99%

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

1998

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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.

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Fine Mapping of the Gene for Carbohydrate-Deficient Glycoprotein Syndrome, Type I (CDG1): Linkage Disequilibrium and Founder Effect in Scandinavian Families

Cited by 51 publications

References 1 publication

The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation

The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation

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

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

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