KLHL40

KLHL40 is a human gene that encodes a member of the Kelch-like protein family. It is part of the BTB-Kelch protein family and functions as a substrate adaptor in Cullin-3 (CUL3) E3 ubiquitin ligase complexes, linking the ligase to specific target proteins for ubiquitination and proteasomal degradation.

In skeletal muscle, KLHL40 contributes to proteostasis and sarcomere integrity by regulating the stability of sarcomeric proteins, including nebulin. By guiding ubiquitination processes, KLHL40 helps maintain proper muscle structure and function. Loss or dysfunction of KLHL40 can disrupt these pathways and compromise muscle fibers.

Mutations in KLHL40 cause a congenital myopathy with nemaline bodies, designated nemaline myopathy 8 (NEM8). Affected individuals typically present with severe hypotonia and weakness from birth, often with respiratory difficulties. Muscle biopsy commonly shows nemaline rods, and nebulin levels in muscle may be reduced. The condition is typically inherited in an autosomal recessive manner, and clinical severity can vary.

Diagnosis is based on clinical findings complemented by genetic testing that identifies biallelic KLHL40 mutations. Management is supportive and multidisciplinary, including physical and respiratory therapy, nutritional support, and monitoring for complications. The understanding of KLHL40’s precise molecular roles in muscle biology continues to evolve, with ongoing research exploring pathways that could inform potential therapies for KLHL40-related myopathies.

KLHL40 is one of several KLHL family proteins that regulate ubiquitination via CUL3 and are linked to distinct muscular diseases, highlighting the importance of ubiquitin-mediated proteostasis in skeletal muscle.