Abstract Book Cover - Weinstein 2012 - University of Chicago

Abstracts
Oral Sessions
Platform Session 1: Human Genetics/CHD Models
S1.1 Deletion of the extracellular matrix protein Adamtsl2 results in a inter-ventricular septal defect in
mice
Dirk Hubmacher, Lauren W.Wang, Suneel S. Apte
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic
Geleophysic dysplasia (GD) is a rare human genetic disorder presenting with short stature, joint contractures
and thick skin. High morbidity, and frequently, juvenile mortality results from cardiac valvular and tracheopulmonary
anomalies. Mutations in the extracellular proteins ADAMTSL2 or fibrillin-1 lead to recessive or
dominant GD, respectively. Excess TGFβ signaling was described in cells derived from GD patients and may
constitute a major pathogenetic mechanism. ADAMTSL2 directly interacts with latent transforming growth factorβ
binding protein (LTBP)-1 and fibrillin-1. Fibrillin-1 and -2 assemble into microfibrils and modulate extracellular
TGFβ and BMP signaling. The Adamtsl2 gene was deleted in mice by an intragenic IRES-lacZ-neomycin
cassette, which also provided an expression reporter. Adamtsl2 deletion resulted in neonatal lethality due to an
inter-ventricular septal defect (VSD) and lung abnormalities. β -gal reporter staining showed Adamtsl2
expression within the embryonic heart and lung, consistent with the observed anomalies. Cardiac expression
was primarily localized to the crest of the inter-ventricular septum, the atrio-ventricular valve annulus and
coronary vessels. Histology revealed a VSD in 80% of the mice with enhanced, localized fibrillin-1 and -2
staining at the crests of the inter-ventricular septum. In vitro, recombinant ADAMTSL2 bound to both fibrillin-1
and -2, and accelerated the biogenesis of fibrillin-1 microfibril formation in fetal bovine nuchal ligament cells,
while blocking fibrillin-2 assembly. This suggests that ADAMTSL2 may provide a mechanism to actively regulate
the ratio of fibrillin-1 to fibrillin-2 in microfibrils, with potential consequences for TGFβ/BMP signaling. These
studies suggest a new role for extracellular matrix in regulation of cardiac development.
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