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Heterozygous deletions within human chromosome 22q11 are the genetic basis of DiGeorge/velocardiofacial syndrome (DGS/VCFS), the most common deletion syndrome (1 in 4,000 live births) in humans 1 . CRKL maps within the common deletion region for DGS/VCFS (ref. 2 ) and encodes an SH2-SH3-SH3 adapter protein closely related to the Crk gene products 3 . Here we report that mice homozygous for a targeted null mutation at the CrkL locus (gene symbol Crkol for mice) exhibit defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac outflow tract, thymus, parathyroid glands and craniofacial structures. We show that the migration and early expansion of neural crest cells is unaffected in Crkol −/− embryos. These results therefore indicate an essential stage- and tissue-specific role for Crkol in the function, differentiation, and/or survival of neural crest cells during development. The similarity between the Crkol −/− phenotype and the clinical manifestations of DGS/VCFS implicate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.

Sarcomere Mutations in Cardiomyopathy With Left Ventricular Hypertrabeculation Lisa M. Dellefave, MS ; Peter Pytel, MD ; Stephanie Mewborn, PhD ; Bassem Mora, MD ; Deborah L. Guris, MD, PhD ; Savitri Fedson, MD ; Darrel Waggoner, MD ; Ivan Moskowitz, MD, PhD and Elizabeth M. McNally, MD, PhD From the Departments of Medicine (L.M.D., S.M., S.F., E.M.M.), Section of Cardiology, Pathology (P.P., I.M.), Surgery (B.M.), Section of Cardiothoracic Surgery, Pediatrics (B.M., D.G., S.F., D.W., I.M.), and Human Genetics (D.W., E.M.M.), The University of Chicago, Chicago, Ill. Correspondence to E. McNally, MD, PhD, 5841 South Maryland, MC6088, Chicago, IL 60637. E-mail emcnally{at}uchicago.edu Received March 2, 2009; accepted July 8, 2009. Background— Mutations in the genes encoding sarcomere proteins have been associated with both hypertrophic and dilated cardiomyopathy. Recently, mutations in myosin heavy chain ( MYH7 ), cardiac actin ( ACTC ), and troponin T ( TNNT2 ) were associated with left ventricular noncompaction, a form of cardiomyopathy characterized with hypertrabeculation that may also include reduced function of the left ventricle. Methods and Results— We used clinically available genetic testing on 3 cases referred for evaluation of left ventricular dysfunction and noncompaction of the left ventricle and found that all 3 individuals carried sarcomere mutations. The first patient presented with neonatal heart failure and was referred for left ventricular noncompaction cardiomyopathy. Genetic testing found 2 different mutations in MYBPC3 in trans . The first mutation, 3776delA, Q1259fs, rendered a frame shift at 1259 of cardiac myosin-binding protein C and the second mutation was L1200P. The frameshift mutation was also found in this mother who displayed mild echocardiographic features of cardiomyopathy, with only subtle increase in trabeculation and an absence of hypertrophy. A second pediatric patient presented with heart failure and was found to carry a de novo MYH7 R369Q mutation. The third case was an adult patient with dilated cardiomyopathy referred for ventricular hypertrabeculation. This patient had a family history of congestive heart failure, including pediatric onset cardiomyopathy where 3 individuals in the family were found to have the MYH7 mutation R1250W. Conclusion— Genetic testing should be considered for cardiomyopathy with hypertrabeculation. Key Words: gene mutation • myosin heavy chain • myosin-binding protein C • sarcomere • cardiomyopathy • contractility • genetics • heart failure • myocardial contraction   CLINICAL PERSPECTIVE Clinical Trial: NCT00138931 Home | Subscriptions | Archives | Feedback | Authors | Help | Circulation Journals Home | AHA Journals Home | Search Copyright © 2009 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. var _rsCI=\"us-lippincott\"; var _rsCG=\"0\"; var _rsDN=\"//secure-us.imrworldwide.com/\"; var _rsSE=1; var _rsSM=1.0;