title: Genetic analysis of familial connective tissue alterations associated with cervical artery dissections suggests locus heterogeneity.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurology, University of Heidelberg, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Wiest
authors.forename: Sonja
authors.initials: S
authors.lastname: Hyrenbach
authors.forename: Pinar
authors.initials: P
authors.lastname: Bambul
authors.forename: Birgit
authors.initials: B
authors.lastname: Erker
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pezzini
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Arnold
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Martin
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelter
authors.forename: Philippe
authors.initials: P
authors.lastname: Lyrer
authors.forename: Otto
authors.initials: O
authors.lastname: Busse
authors.forename: Tobias
authors.initials: T
authors.lastname: Brandt
authors.forename: Caspar
authors.initials: C
authors.lastname: Grond-Ginsbach
mesh_terms: D000328:Adult; D000368:Aged; D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000784:Aortic Dissection / Q000150:complications / Q000235:genetics* / Q000473:pathology; D001706:Biopsy; D020215:Carotid Artery, Internal, Dissection / Q000235:genetics; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003238:Connective Tissue / Q000473:pathology*; D003240:Connective Tissue Diseases / Q000150:complications / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012867:Skin / Q000473:pathology; D020521:Stroke / Q000209:etiology*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000594:Amino Acid Oxidoreductases; D011508:Chondroitin Sulfate Proteoglycans; D008565:Membrane Proteins; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4; C445313:LOXL1 protein, human