Abstract
Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades. Advances in approaches to genetics and genomics have aided in the identification of new pathogenic mechanisms in rare genetic disorders and have opened up new avenues for therapeutic interventions by identification of new molecular pathways in muscle disease. Recent studies have identified mutations of several Kelch proteins in skeletal muscle disorders. The Kelch superfamily is one of the largest evolutionary conserved gene families. The 66 known family members all possess a Kelch-repeat containing domain and are implicated in diverse biological functions. In skeletal muscle development, several Kelch family members regulate the processes of proliferation and/or differentiation resulting in normal functioning of mature muscles. Importantly, many Kelch proteins function as substrate-specific adaptors for Cullin E3 ubiquitin ligase (Cul3), a core component of the ubiquitin-proteasome system to regulate the protein turnover. This review discusses the emerging roles of Kelch proteins in skeletal muscle function and disease.
Highlights
Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades
Kelch proteins belong to the Kelch superfamily that consists of a large number of structurally and functionally diverse proteins characterized by the presence of a Kelch-repeat domain [23,24]
This review summarizes our emerging understanding of the various roles of Kelch proteins in skeletal muscle development and disease (Tables 1 and 2)
Summary
Recent developments in gene discovery have led to the identification of Kelch family members as regulators of skeletal muscle development and function. Authors’ contribution VAG and AHB wrote the manuscript Both authors read and approved the final manuscript. Authors’ information Alan H Beggs, PhD is Sir Edwin and Lady Manton Professor of Pediatrics at Harvard Medical School and Research Associate in the Division of Genetics and Genomics at Boston Children’s Hospital where he is director of The Manton Center for Orphan Disease Research. Dr Beggs has been associated with the discovery of several new genes associated with congenital muscle diseases as well as developing gene and protein based therapies for X-linked myotubular myopathy. Vandana A Gupta, PhD is an Instructor in Pediatrics at Harvard Medical School and Associate Research Staff in the Division of Genetics and Genomics at Boston Children’s Hospital.
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