ABSTRACT
To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.
Subject(s)
Cognition/physiology , DNA-Binding Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Visual Perception/genetics , Williams Syndrome/genetics , Base Sequence , Blotting, Northern , Brain/embryology , Brain/growth & development , Brain/physiology , Chromosome Aberrations , Chromosomes, Human, Pair 7/genetics , Elastin/genetics , Gene Deletion , Gene Expression Regulation, Developmental/physiology , Humans , In Situ Hybridization, Fluorescence , Lim Kinases , Molecular Sequence Data , Phenotype , Protein Kinases/genetics , Sequence Analysis, DNA , Zinc Fingers/geneticsABSTRACT
Supravalvular aortic stenosis (SVAS) is an inherited vascular disease that can cause heart failure and death. SVAS can be inherited as an autosomal dominant trait or as part of a developmental disorder, Williams syndrome (WS). In recent studies we presented evidence suggesting that a translocation disrupting the elastin gene caused SVAS in one family while deletions involving the entire elastin locus caused WS. In this study, pulsed-field, PCR, and Southern analyses showed that a 100-kb deletion of the 3' end of the elastin gene cosegregated with the disease in another SVAS family. DNA sequence analysis localized the breakpoint between elastin exons 27 and 28, the same region disrupted by the SVAS-associated translocation. These data indicate that mutations in the elastin gene cause SVAS and suggest that elastin exons 28-36 may encode critical domains for vascular development.
Subject(s)
Aortic Stenosis, Subvalvular/genetics , Elastin/genetics , Gene Deletion , Base Sequence , Electrophoresis, Gel, Pulsed-Field , Female , Humans , Male , Molecular Sequence Data , MutationABSTRACT
Williams syndrome (WS) is a developmental disorder affecting connective tissue and the central nervous system. A common feature of WS, supravalvular aortic stenosis, is also a distinct autosomal dominant disorder caused by mutations in the elastin gene. In this study, we identified hemizygosity at the elastin locus using genetic analyses in four familial and five sporadic cases of WS. Fluorescent in situ hybridization and quantitative Southern analyses confirmed these findings, demonstrating inherited and de novo deletions of the elastin gene. These data indicate that deletions involving one elastin allele cause WS and implicate elastin hemizygosity in the pathogenesis of the disease.
Subject(s)
Connective Tissue Diseases/genetics , Developmental Disabilities/genetics , Elastin/genetics , Adult , Alleles , Aortic Valve Stenosis/genetics , Arteries/abnormalities , Blotting, Southern , Child , Child, Preschool , Chromosomes, Human, Pair 7 , Genes , Genotype , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability/genetics , Pedigree , Sequence Deletion , SyndromeABSTRACT
To identify genes involved in vascular disease, we investigated patients with supravalvular aortic stenosis (SVAS), an inherited vascular disorder that causes hemodynamically significant narrowing of large elastic arteries. Pulsed-field gel and Southern analyses showed that a translocation near the elastin gene cosegregated with SVAS in one family. DNA sequence analyses demonstrated that the translocation disrupted the elastin gene and localized the breakpoint to exon 28. Taken together with our previous study linking SVAS to the elastin gene in two additional families and existing knowledge of vascular biology, these data suggest that mutations in the elastin gene can cause SVAS.
Subject(s)
Aortic Valve Stenosis/genetics , Elastin/genetics , Amino Acid Sequence , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 6 , Chromosomes, Human, Pair 7 , Female , Genetic Linkage , Humans , Hybrid Cells , Male , Molecular Sequence Data , Pedigree , Polymorphism, Restriction Fragment Length , Syndrome , Translocation, GeneticABSTRACT
The pathogenesis of vascular disease is unclear, but genetic factors play an important role. In this study we performed linkage analyses in two families with supravalvular aortic stenosis, an inherited vascular disorder that causes narrowing of major arteries and may lead to cardiac overload and failure. DNA markers on the long arm of chromosome 7 (D7S371, D7S395, D7S448, and ELN) were linked to supravalvular aortic stenosis in both families with a combined logarithm of likelihood for linkage (lod score) of 5.9 at the ELN locus. These findings indicate that a gene for supravalvular aortic stenosis is located in the same chromosomal subunit as elastin, which becomes a candidate for the disease gene.
