Genetic analysis of familial connective tissue alterations associated with cervical artery dissections suggests locus heterogeneity.
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.
Wiest
Tina
T
Department of Neurology, University of Heidelberg, Germany.
Hyrenbach
Sonja
S
Bambul
Pinar
P
Erker
Birgit
B
Pezzini
Alessandro
A
Hausser
Ingrid
I
Arnold
Marie-Luise
ML
Martin
Juan José
JJ
Engelter
Stefan
S
Lyrer
Philippe
P
Busse
Otto
O
Brandt
Tobias
T
Grond-Ginsbach
Caspar
C
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
D000594:Amino Acid Oxidoreductases; D011508:Chondroitin Sulfate Proteoglycans; D008565:Membrane Proteins; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4; C445313:LOXL1 protein, human