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.
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 ofa 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. (J. Clin. Invest. 1994.
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.
Source/Description: Cosmid 7G4 spans the NotI site distal to the NFI translocation breakpoint t( 17; 22) and is part of an overlapping series of cosmids identified by clone c 1-1F 10. An 8 kb BglII fragment (f7G4-GL.2) from cosmid 7G4 detects the BglII RFLP system. Polymorphism: BglII identifies a two-allele polymorphism with
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