Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome

Zaghloul N.A.; Liu Y.; Gerdes J.M.Gascue C.Oh E.C.Leitch C.C.Bromberg Y.Binkley J.Leibel R.L.Sidow A.Badano J.L.Katsanis N.

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Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome

机译：Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome

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Technological advances hold the promise of rapidly catalyzing the discovery of pathogenic variants for genetic disease. However, this possibility is tempered by limitations in interpreting the functional consequences of genetic variation at candidate loci. Here, we present a systematic approach, grounded on physiologically relevant assays, to evaluate the mutational content (125 alleles) of the 14 genes associated with Bardet-Biedl syndrome (BBS). A combination of in vivo assays with subsequent in vitro validation suggests that a significant fraction of BBS-associated mutations have a dominant-negative mode of action. Moreover, we find that a subset of common alleles, previously considered to be benign, are, in fact, detrimental to protein function and can interact with strong rare alleles to modulate disease presentation. These data represent a comprehensive evaluation of genetic load in a multilocus disease. Importantly, superimposition of these results to human genetics data suggests a previously underappreciated complexity in disease architecture that might be shared among diverse clinical phenotypes.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第23期|10602-10607|共6页
作者
Zaghloul N.A.; Liu Y.; Gerdes J.M.Gascue C.Oh E.C.Leitch C.C.Bromberg Y.Binkley J.Leibel R.L.Sidow A.Badano J.L.Katsanis N.;
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作者单位

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States;

Institut Pasteur de Montevideo, CP11400 Montevideo, Uruguay;

Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27708, United StatesDepartment of Biochemistry and Molecular Biophysics, Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, United StatesDepartment of Genetics, Stanford University Medical Center, Stanford, CA 94305, United StatesDivision of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Ciliopathy; Epistasis; In vivo assays; Zebrafish;

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome

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