title: Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation.
abstract: 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.
authors: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Silvia E
authors: SE
authors: Racedo
authors: Division of Genetics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Donna M
authors: DM
authors: McDonald-McGinn
authors: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Jonathan H
authors: JH
authors: Chung
authors: Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Elizabeth
authors: E
authors: Goldmuntz
authors: Division of Genetics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Elaine
authors: E
authors: Zackai
authors: Division of Genetics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Beverly S
authors: BS
authors: Emanuel
authors: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Bin
authors: B
authors: Zhou
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine, Cambridge, MA 02139, USA.
authors: Birgit
authors: B
authors: Funke
authors: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA. Electronic address: bernice.morrow@einstein.yu.edu.
authors: Bernice E
authors: BE
authors: Morrow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004452:Echocardiography; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D056916:Segmental Duplications, Genomic / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins