Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements.

Stoppa‐Lyonnet, Dominique; Carter, Philip E.; Meo, Tommaso; Tosi, Mario

doi:10.1073/pnas.87.4.1551

Cited by 153 publications

(75 citation statements)

References 33 publications

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“…A correlation between sequence content and genetic instability has been noted at several common sites of DNA rearrangement in the human population: A significant fraction lie within regions occupied by locally reiterated sequences (e.g., Stoppa-Lyonnet et al 1990;Saleh et al 1992;Rabbitts 1994;Dutly and Schnitzel 1996;van Deutekom et al 1996). Exactly how repeated sequences might serve to facilitate rearrangement is uncertain, but strong evidence of illegitimate inter-and intrachromosomal recombination events has been obtained in several cases (e.g., Kulozik et al 1992;Dutly and Schnitzel 1996;van Deutekom et al 1996;Kehrer-Sawatski et al 1997).…”

Section: Homology Region Bordersmentioning

confidence: 99%

Zooming in on the Human–Mouse Comparative Map: Genome Conservation Re-examined on a High-Resolution Scale

Carver¹,

Stubbs²

1997

Genome Res.

117

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Over the past decade, conservation of genetic linkage groups has been shown in mammals and used to great advantage, fueling significant exchanges of gene mapping and functional information especially between the genomes of humans and mice. As human physical maps increase in resolution from chromosome bands to nucleotide sequence, comparative alignments of mouse and human regions have revealed striking similarities and surprising differences between the genomes of these two best-mapped mammalian species. Whereas, at present, very few mouse and human regions have been compared on the physical level, existing studies provide intriguing insights to genome evolution, including the observation of recent duplications and deletions of genes that may play significant roles in defining some of the biological differences between the two species. Although high-resolution conserved marker-based maps are currently available only for human and mouse, a variety of new methods and resources are speeding the development of comparative maps of additional organisms. These advances mark the first step toward establishment of the human genome as a reference map for vertebrate species, providing evolutionary and functional annotation to human sequence and vast new resources for genetic analysis of a variety of commercially, medically, and ecologically important animal models.

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Section: Homology Region Bordersmentioning

confidence: 99%

Zooming in on the Human–Mouse Comparative Map: Genome Conservation Re-examined on a High-Resolution Scale

Carver¹,

Stubbs²

1997

Genome Res.

117

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“…However, due to the high incidence (~20%) of large deletions and insertions caused by the intragenic Alu sequences Stoppa-Lyonnet et al, 1990], a complete diagnostic strategy likely involves the examination of the large rearrangements.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema

Kalmár¹,

Bors²,

Farkas

et al. 2003

Hum. Mutat.

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Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema caused by the deficiency of activated C1 esterase inhibitor protein (C1-INH, type I (C1NH): reduced serum antigen level, type II: reduced activity and normal serum antigen level). The aim of the present study was to determine the disease-causing mutations in the C1INH gene (SERPING1) among Hungarian HAE-patients. The estimated number of affected HAE-families in Hungary is 40-50, out of which 26 families (type I:23, type II:3) managed in a single center were enrolled in the current study. To detect large deletions/insertions, we used Southern-blotting analysis followed by real time PCR based gene dosage analysis. In the absence of large structural changes, we employed direct sequencing covering the whole coding region and splicing sites of the C1INH gene. Large deletions were detected in 4/23 (17.4%) type I families. We found the g.16788C>T (p.Arg444Cys) mutation in each 3, type II HAE-families. In the remaining type

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“…Alu sequences are distributed throughout all chromosomes occurring mostly in intergenic region and introns, but occasionally in the 3'-untranslated regions of mRNAs as in the LDL receptor (6). The large number of Alu repeats in the human genomes, coupled with their capacity to be transcribed into RNA, has led to the idea that these sequences might serve as sites for genome rearrangements (22). This hypothesis has received its strongest support from the almost invariant finding of Alu sequence at the function of large rearrangements in the LDL receptor gene (16).…”

Section: Genetic Defects In Ldl Receptormentioning

confidence: 99%

“…This twofold increase may be significant. It seems likely that the number of rearrangements in a region of DNA may rise in geometric fashion with the number of Alu sequence, each of which may act as a hot spot for recombination (22). A few possible mutations result from a cytosine (C) to thymidine (T) transition at a CpG dinucleotid~, a frequent cause of mutations in the human genome (23).…”

Section: Genetic Defects In Ldl Receptormentioning

confidence: 99%

Molecular basis of familial hypercholesterolemia: An Indian experience

Ashavaid

Altaf

Nair

2000

Indian J Clin Biochem

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Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by a multitude of low-density lipoprotein (LDL) receptor gene mutations. The LDL receptor is a cell surface trans-membrane protein that mediates the uptake & lysosomal degradation of plasma LDI., thereby providing cholesterol to cells. Affected individuals have elevated plasma levels of LDL, which causes premature coronary atherosclerosis. FH has an estimated worldwide prevalence of 0.2%. In some subpopulations there is an increased frequency of FH and specific LDL receptor mutations are found to be common due to 'founder gene effect'. Overall, more than 300 naturally occurring LDL receptor mutations have been described. To date upto ten LDL receptor gene mutations have been identified in Indians in South Africa, suggesting increased incidence of FH among Indians. Most mutations have occurred at CpG dinucleotide, a mutational hotspot in human genetic disease.In our study in 25 hypercholesterolemic subjects we have identified two novel insertion mutations in two patients. But the mutations underlying FH are still undefined in the majority of cases. Mutational heterogeneity on the other-hand has complicated disease diagnosis at DNA level. These findings warrant application of a generalized mutation screening method in search for new LDL receptor gene defects.

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Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements.

Abstract: Frequent alterations in the structure of the complement component C1 inhibitor gene

Cited by 153 publications

References 33 publications

Zooming in on the Human–Mouse Comparative Map: Genome Conservation Re-examined on a High-Resolution Scale

Zooming in on the Human–Mouse Comparative Map: Genome Conservation Re-examined on a High-Resolution Scale

Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema

Molecular basis of familial hypercholesterolemia: An Indian experience

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