Journal article

Publication year: 2022

Pages: 226-237

Journal: Molecular Genetics and Metabolism

Volume number: 136

Issue number: 3

ISSN: 1096-7192

eISSN: 1096-7206

DOI Link: https://doi.org/10.1016/j.ymgme.2022.05.005

Publisher: Elsevier

Abstract: 
Popeye domain containing protein 1 (POPDC1) is a highly conserved transmembrane protein essential for striated muscle function and homeostasis. Pathogenic variants in the gene encoding POPDC1 (BVES, Blood vessel epicardial substance) are causative for limb-girdle muscular dystrophy (LGMDR25), associated with cardiac arrhythmia. We report on four affected children (age 7-19 years) from two consanguineous families with two novel pathogenic variants in BVES c.457C>T(p.Q153X) and c.578T>G (p.I193S). Detailed analyses were performed on muscle biopsies from an affected patient of each family including immunofluorescence, electron microscopy and proteomic profiling. Cardiac abnormalities were present in all patients and serum creatine kinase (CK) values were variably elevated despite lack of overt muscle weakness. Detailed histological analysis of skeletal muscle, however indicated a myopathy with reduced sarcolemmal expression of POPDC1 accompanied by altered sarcolemmal and sarcoplasmatic dysferlin and Xin/XIRP1 abundance. At the electron microscopic level, the muscle fiber membrane was focally disrupted. The proteomic signature showed statistically significant dysregulation of 191 proteins of which 173 were increased and 18 were decreased. Gene ontology-term analysis of affected biological processes revealed -among others -perturbation of muscle fibril assembly, myofilament sliding, and contraction as well as transition between fast and slow fibers. In conclusion, these findings demonstrate that the phenotype of LGMDR25 is highly variable and also includes younger children with conduction abnormalities, no apparent muscular problems, and only mildly elevated CK values. Biochemical studies suggest that BVES mutations causing loss of functional POPDC1 can impede striated muscle function by several mechanisms. (c) 2022 Elsevier Inc. All rights reserved.

Harvard Citation style: Gangfuss, A., Hentschel, A., Heil, L., Gonzalez, M., Schoenecker, A., Depienne, C., et al. (2022) Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1), Molecular Genetics and Metabolism, 136(3), pp. 226-237. https://doi.org/10.1016/j.ymgme.2022.05.005

APA Citation style: Gangfuss, A., Hentschel, A., Heil, L., Gonzalez, M., Schoenecker, A., Depienne, C., Nishimura, A., Zengeler, D., Kohlschmidt, N., Sickmann, A., Schara-Schmidt, U., Fuerst, D., Ven, P., Hahn, A., Roos, A., & Schaenzer, A. (2022). Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1). Molecular Genetics and Metabolism. 136(3), 226-237. https://doi.org/10.1016/j.ymgme.2022.05.005