Association of Limb-Girdle Muscular Dystrophy with Pathogenic Mutations in a nuclear mitochondrial gene

Topic:

Ultra-Rare myopathies and dystrophies (<1:100,000 worldwide)

Poster Number: 205

Author(s):

Dorianmarie Vargas Franco, PhD, Chengcheng Li, PhD, Christine Bruels, PhD, Andrea L. Reid, PhD, Lynn Pais, Elicia Estrella, MS, LCGC, Sherifa A. Hamed, MD, Safoora Syeda, MBBS, Raghav Kalra, Hart G.W. Lidov, MD, PhD, Anne O’Donnell, MD, PhD, Basil Darras, MD, Louis Kunkel, PhD, Isabelle Draper, PhD, Matthew Alexander, PhD, Christina Pacak, PhD, Peter Kang, MD

Institutions:

1. University of Florida College of Medicine, 3. University of Florida - Pediatric Neurology, 4. University of Alabama Birmingham and Children’s Alabama, 5. Broad Institute of the Massachusetts Institute of Technology and Harvard University, 6. Boston Children’s Hospital and Harvard Medical School, 7. Assiut University Hospital, 9. University of Florida College of Medicine, 10. Boston Children’s Hospital and Harvard Medical School, 11. Broad Institute of the Massachusetts Institute of Technology and Harvard University, 12. Boston Children's Hospital, 13. Boston Children's Hospital - Harvard Medical School, 14. Tufts Medical Center, 15. Children's of Alabama/University of Alabama at Birmingham, 16. UF - College of Medicine - Dept. of Pediatrics, 17. UF - College of Medicine - Dept. of Molecular Genetics and Microbiology

Numerous cases of limb-girdle muscular dystrophy (LGMD) remain without genetic diagnoses, despite the stunning genetic advances of recent decades. We conducted exome sequencing on a cohort of unsolved LGMD subjects, with follow-up investigations that included Sanger sequencing, quantitative PCR, and zebrafish studies. In two unrelated probands with sporadic LGMD phenotypes, these analyses revealed and confirmed compound heterozygous putative pathogenic mutations for a nuclear mitochondrial gene not previously associated with a human disease. Dramatic reductions in gene expression were confirmed on RNA derived from muscle biopsy samples representing the two probands. Knockdown of the gene in human myoblast culture was associated with abnormal mitochondrial cellular distribution. Knockdown of the homologous gene in zebrafish was associated with reduced motility. In aggregate, these results support the causative role of mutations in this nuclear mitochondrial gene in a subset of patients with LGMD.