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Genetic analysis of familial connective tissue alterations associated with cervical artery dissections suggests locus
Tina Wiest1, Sonja Hyrenbach, Pinar Bambul
1Department of Neurology, University of Heidelberg, Germany.
Insights
Genetic linkage studies in families with cervical artery dissection (CAD) suggest a familial connective tissue disorder. While candidate loci on chromosomes 15q24 and 10q26 were identified, no specific gene mutation was found, indicating potential locus heterogeneity.
Area of Science:
- Genetics
- Molecular Biology
- Vascular Medicine
Background:
- Cervical artery dissections (CAD) are linked to connective tissue abnormalities.
- These connective tissue phenotypes appear to be familial, with an autosomal dominant inheritance pattern.
Purpose of the Study:
- To investigate the genetic basis of connective tissue aberrations associated with CAD.
- To identify potential genetic loci and causative genes for familial CAD.
Main Methods:
- Genetic linkage studies were conducted in three families with CAD.
- Connective tissue phenotypes were assessed via electron microscopy of skin biopsies.
- Genome-wide linkage analysis and sequence analysis of candidate genes were performed.
Main Results:
- Linkage analysis suggested candidate loci on chromosome 15q24 (Z=+2.1) and 10q26 (Z=+1.9) in one family.
- Sequence analysis of CSPG4, LOXL1, and FGFR2 genes did not reveal causative mutations.
- Linkage on chromosomes 15q24 and 10q26 was excluded in two additional families.
Conclusions:
- A familial connective tissue phenotype associated with CAD may involve genetic loci on chromosomes 15q24 or 10q26.
- No specific gene mutation was identified in the studied loci.
- Locus heterogeneity is suggested for the connective tissue phenotype in CAD patients.
Background And Purpose:
Cervical artery dissections (CAD) can be associated with connective tissue aberrations in skin biopsies. The analysis of healthy relatives of patients suggested that the connective tissue phenotype is familial with an autosomal dominant inheritance.
Methods:
We performed genetic linkage studies in 3 families of patients with CAD. Connective tissue phenotypes for the patients and all family members were assessed by electron microscopic study of skin biopsies. A genome-wide linkage analysis of 1 family (1 patient with 8 healthy relatives) indicated 2 candidate loci. Three genes were subsequently studied by sequence analysis. Part of the genome was also studied by linkage analysis in 2 further families.
Results:
The genome-wide scan in a single family suggested linkage between the hypothetical mutation causing the connective tissue phenotype and informative genetic markers on chromosome 15q24 (logarithm of the odds score: Z= +2.1). A second possible candidate locus (Z=+1.9) was found on chromosome 10q26. Sequence analysis of 3 candidate genes in the suggestive locus (chondroitin sulfate proteoglycan4 [CSPG4], lysyl oxidase-like1 [LOXL1] and fibroblast growth factor receptor2 [FGFR2]) did not lead to the identification of a mutation responsible for connective tissue alterations. In 2 additional smaller families the loci on chromosome 15q24 and 10q26 were excluded by linkage analysis.
Conclusions:
Linkage analysis of a large family with CAD-associated connective tissue alterations suggested the presence of a candidate locus on chromosome 15q2 or on chromosome 10q26. Sequence analysis did not lead to the identification of a mutated candidate gene in 1 of these loci. The study of 2 additional pedigrees indicated locus heterogeneity for the connective tissue phenotype of CAD patients.
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