Abstract:

Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. Sanger sequencing of 116 unrelated individuals with NM identified compound heterozygous changes in KLHL41 in a fifth family. Mutations in KLHL41 showed a clear phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. Functional studies in zebrafish showed that loss of Klhl41 results in highly diminished motor function and myofibrillar disorganization, with nemaline body formation, the pathological hallmark of NM. These studies expand the genetic heterogeneity of NM and implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity in NM.

日本語要旨:

ネマリンミオパチー(NM)患者の全エクソンシークエンスを行いBTB-Kelch蛋白をコードするKLHL41(Kelch-like family memmber)遺伝子変異を検出した。変異形式により重症度が異なり、遺伝型と表現型の相関性が認められた。ゼブラフィッシュによる変異遺伝子蛋白の機能解析では、運動機能低下、筋原線維配列の乱れ、ネマリン小体形成などのNMの所見が認められた。BTB-Kelch蛋白の異常はNMのサルコメア構造異常の原因となることが証明された。