Next-generation sequencing is commonly used to screen for pathogenic mutations in families with Mendelian disorders, but due to the pace of discoveries, gaps have widened for some diseases between genetic and pathophysiological knowledge. We recruited and analyzed 16 families with limb-girdle muscular dystrophy (LGMD) of Arab descent from Saudi Arabia and Sudan who did not have confirmed genetic diagnoses. The analysis included both traditional and next-generation sequencing approaches. Cellular and metabolic studies were performed on Pyroxd1 siRNA C2C12 myoblasts and controls. Pathogenic mutations were identified in eight of the 16 families. One Sudanese family of Arab descent residing in Saudi Arabia harbored a homozygous c.464A>G, p.Asn155Ser mutation in PYROXD1, a gene recently reported in association with myofibrillar myopathy and whose protein product reduces thiol residues. Pyroxd1 deficiency in murine C2C12 myoblasts yielded evidence for impairments of cellular proliferation, migration, and differentiation, while CG10721 (Pyroxd1 fly homolog) knockdown in Drosophila yielded a lethal phenotype. Further investigations indicated that Pyroxd1 does not localize to mitochondria, yet Pyroxd1 deficiency is associated with decreased cellular respiration. This study identified pathogenic mutations in half of the LGMD families from the cohort, including one in PYROXD1. Developmental impairments were demonstrated in vitro for Pyroxd1 deficiency and in vivo for CG10721 deficiency, with reduced metabolic activity in vitro for Pyroxd1 deficiency.
|Original language||English (US)|
|Number of pages||11|
|State||Published - Nov 2018|
Bibliographical noteFunding Information:
This study was funded by National Institutes of Health (NIH) Grant R01 NS-080929 (M. Saha, H. M. Reddy, P. B. Kang) and the Bernard F. and Alva B. Gimbel Foundation (L. M. Kunkel). Exome sequencing and analysis was provided by the Broad Institute of MIT and Harvard that was supported by NIH Grant U54 HG-003067 (Eric Lander). M. A. Salih was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia via research group project number RGP-VPP-301.
Dr. MacArthur is a founder with equity holdings in Goldfinch Bio. Dr. Kunkel is on the scientific advisory boards of Sarepta Therapeutics and Summit Therapeutics. Dr. Kang holds a grant from the National Institute for Neurological Disorders and Stroke of the NIH, consults for AveXis, is a co-investigator for Catabasis, receives royalties from Springer for a textbook, serves as an associate editor for Muscle & Nerve and thus receives honoraria from Wiley, and has authored chapters for UpToDate and thus receives honoraria from Wolters Kluwer.
© 2018 the American Physiological Society.
- Exome sequencing
- Limb-girdle muscular dystrophy