Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation.

Autor:	Racedo SE; Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA., McDonald-McGinn DM; Division of Genetics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Chung JH; Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA., Goldmuntz E; Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Zackai E; Division of Genetics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Emanuel BS; Division of Genetics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Zhou B; Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA., Funke B; Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine, Cambridge, MA 02139, USA., Morrow BE; Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA. Electronic address: bernice.morrow@einstein.yu.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2015 Feb 05; Vol. 96 (2), pp. 235-44.
DOI:	10.1016/j.ajhg.2014.12.025
Abstrakt:	The human chromosome 22q11.2 region is susceptible to rearrangements during meiosis leading to velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome (22q11DS) characterized by conotruncal heart defects (CTDs) and other congenital anomalies. The majority of individuals have a 3 Mb deletion whose proximal region contains the presumed disease-associated gene TBX1 (T-box 1). Although a small subset have proximal nested deletions including TBX1, individuals with distal deletions that exclude TBX1 have also been identified. The deletions are flanked by low-copy repeats (LCR22A, B, C, D). We describe cardiac phenotypes in 25 individuals with atypical distal nested deletions within the 3 Mb region that do not include TBX1 including 20 with LCR22B to LCR22D deletions and 5 with nested LCR22C to LCR22D deletions. Together with previous reports, 12 of 37 (32%) with LCR22B-D deletions and 5 of 34 (15%) individuals with LCR22C-D deletions had CTDs including tetralogy of Fallot. In the absence of TBX1, we hypothesized that CRKL (Crk-like), mapping to the LCR22C-D region, might contribute to the cardiac phenotype in these individuals. We created an allelic series in mice of Crkl, including a hypomorphic allele, to test for gene expression effects on phenotype. We found that the spectrum of heart defects depends on Crkl expression, occurring with analogous malformations to that in human individuals, suggesting that haploinsufficiency of CRKL could be responsible for the etiology of CTDs in individuals with nested distal deletions and might act as a genetic modifier of individuals with the typical 3 Mb deletion. (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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