Exome sequencing identifies PINCH2 mutations associated with early-onset autosomal recessive LGMD with severe cardiomyopathy and triangular tongue. J. Warman Chardon1, A. Smith2, J. Woulfe3, K. Rakhra4, C. Dennie4, J. Schwartzentruber5, C. Beaulieu2, FORGE. Canada Consortium6, J. Majewski7, D. E. Bulman2, K. M. Boycott1,2, D. Dyment1,2 1) Genetics, Chidren's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 2) Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; 3) Pathology, The Ottawa Hospital, Ottawa, Ontario, Canada; 4) Medical Imaging, The Ottawa Hospital, Ottawa, Ontario, Canada; 5) McGill University and Genome Quebec Innovation Centre, Montréal, Québec; 6) Canada; 7) Department of Human Genetics, McGill University, Montreal, Quebec.

   Limb Girdle Muscular Dystrophy (LGMD) is a heterogeneous group of inherited disorders leading to progressive muscle degeneration often associated with cardiac complications. We investigated affected siblings with a childhood onset LGMD with macroglossia and calf enlargement. The siblings developed decreased ejection fraction with global left ventricular dysfunction in their 3rd decade, severe quadriparesis and relative sparing of the face, with a broad based triangular tongue. After negative genetic evaluation for known LGMD genes, we performed whole exome sequencing of the affected siblings and identified shared compound heterozygous missense mutations in exon 5 (c.C356T; p.Pro119Leu and c.C342G; p.Asn114Lys) and exon 11 (c.T1034C; p.Leu345Pro) of the PINCH2 gene, which segregated appropriately in the family. Both novel variants in exon 5 are in cis. PINCH2 is an important member of the IPP (ILK, Parvin, PINCH) heterotrimeric complex and is essential for signaling through integrin adhesion receptors that regulate cell migration, spreading and adhesion and is found in skeletal and cardiac muscle cells. The IPP complex stabilizes expression of the component proteins by reducing proteasomal degradation. PINCH1 and PINCH2 demonstrate overlapping expression, competitive binding to ILK and functional redundancy. There is evidence in murine models that PINCH1 may compensate for loss of PINCH2 in some tissues, suggesting that a potential therapeutic approach may involve upregulation of PINCH1 to stabilize the IPP complex in patients with PINCH2 mutations. Although well demonstrated in animal models, this is a novel discovery of IPP complex dysfunction implicated in LGMD.

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