Mutation in KERA Identified by Linkage Analysis and Targeted Resequencing in a Pedigree with Premature AtherosclerosisReport as inadecuate




Mutation in KERA Identified by Linkage Analysis and Targeted Resequencing in a Pedigree with Premature Atherosclerosis - Download this document for free, or read online. Document in PDF available to download.

Aims

Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis.

Methods and Results

Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA c.920C>G; p.Ser307Cys was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe−-− mice r2 = 0.69; p<0.0001.

Conclusion

A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis.



Author: Stephanie Maiwald , Suthesh Sivapalaratnam , Mahdi M. Motazacker , Julian C. van Capelleveen, Ilze Bot, Saskia C. de Jager, Miran

Source: http://plos.srce.hr/



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