Akademik Veri Yönetim Sistemi
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, cilt.23, sa.21, 2022 (SCI-Expanded)
Lamina-associated polypeptide 1 (LAP1) is a ubiquitously expressed inner nuclear membrane protein encoded by TOR1AIP1, and presents as two isoforms in humans, LAP1B and LAP1C. While loss of both isoforms results in a multisystemic progeroid-like syndrome, specific loss of LAP1B causes muscular dystrophy and cardiomyopathy, suggesting that LAP1B has a critical role in striated muscle. To gain more insight into the molecular pathophysiology underlying muscular dystrophy caused by LAP1B, we established a patient-derived fibroblast line that was transdifferentiated into myogenic cells using inducible MyoD expression. Compared to the controls, we observed strongly reduced myogenic differentiation and fusion potentials. Similar defects were observed in the C2C12 murine myoblasts carrying loss-of-function LAP1A/B mutations. Using RNA sequencing, we found that, despite MyoD overexpression and efficient cell cycle exit, transcriptional reprogramming of the LAP1B-deficient cells into the myogenic lineage is impaired with delayed activation of MYOG and muscle-specific genes. Gene set enrichment analyses suggested dysregulations of protein metabolism, extracellular matrix, and chromosome organization. Finally, we found that the LAP1B-deficient cells exhibit nuclear deformations, such as an increased number of micronuclei and altered morphometric parameters. This study uncovers the phenotypic and transcriptomic changes occurring during myoconversion of patient-derived LAP1B-deficient fibroblasts and provides a useful resource to gain insights into the mechanisms implicated in LAP1B-associated nuclear envelopathies.