Abstract:

Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.

日本語要旨:

ネマリンマイオパチーの新規原因遺伝子としてLMOD3を報告した。エクソーム解析とサンガーシーケンスにより、本遺伝子の常染色体劣性変異が15家系に見出された。また、LMOD3がアクチンフィラメントを伸長することが示された。本患者において、アクチンフィラメントの短縮が確認された。これらの結果からLMOD3の機能喪失変異は、アクチンフィラメントの短縮を引き起こし、ネマリンマイオパチーを発症すると考えられた。