- An international consortium coordinated by a group from the IIBM has identified pathogenic genetic variants in the CACNB1 gene as a new cause of hereditary muscle disease
The Laboratory of Genetics and Pathophysiological Mechanisms of Congenital Anomalies of the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM) CSIC-UAM, member of the CIBERER consortium and led by Dr. Víctor L. Ruíz-Pérez, has coordinated a study that demonstrates, for the first time, that mutations in the CACNB1 gene are the cause of a congenital muscular disorder of genetic origin. The work, recently published in the journal European Journal of Human Genetics, has been carried out in collaboration with various national and international groups.
The article describes three patients diagnosed with a congenital myopathy characterized by predominant involvement of proximal muscles, severe muscle weakness, elevated blood creatine kinase levels and low body weight. Using next-generation sequencing techniques, the authors identified in the patients of the study different mutations in the CACNB1 gene, which until now had not been associated with any genetic disease.
CACNB1 encodes the β1 subunit of voltage-dependent calcium channels. Within this family of channels is the dihydropyridine receptor (DHPR), which plays a key role in the skeletal muscle contraction.
The researchers used a variant of the CRISPR-Cas9 gene-editing system to modify the genome of a human myoblast cell line and faithfully replicate one of the mutations detected in one of the patients. The analysis of these “avatar” cells showed that the mutation introduced in CACNB1 significantly reduced the levels of the main subunit α1s of the DHPR protein, whose deficiency is a known cause of congenital myopathy.
“We hope that this work may benefit other patients with with a similar condition who do not yet have a genetic diagnosis,” said Asier Iturrate, first author of the paper and predoctoral researcher of the group at the IIBM. “We propose adding this gene to panels of rare neuromuscular diseases, and we encourage other groups working in the field to test the CACNB1 gene in their unresolved cases.”
Reference of the article: Iturrate A, Assia Batzir N, Jaron R, Garcia-Valentin D, Nevado J, Tenorio-Castano J, Lapunzina P, Lee K, Greenberg R, Sassi D, Aharoni S, Kuzminsky A, Basel-Salmon L, Orenstein N, Fellig Y, Ben-Shachar S, Marek-Yagel D, Ruiz-Perez VL. N-terminal truncating variants in CACNB1 cause a new congenital muscular disorder. Eur J Hum Genet. (2025) https://doi.org/10.1038/s41431-025-01944-4
Cover image: Confocal microscopy image of cultured myotubes differentiated from human LHCN-M2 myoblasts, showing co-localization of the dihydropyridine receptor (DHPR, in red) with the ryanodine receptor (RYR1, in green).