Kelch proteiinit lihastaudeissa (2014 katsaus, V.A. Gupta, A.H. Beggs)

PÄIVITYSHAKU   KELCH proteins and skeletal muscle

https://pubmed.ncbi.nlm.nih.gov/?term=Kelch+proteins+and+Sceletal+muscle+

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067060/
  Skelet Muscle. 2014; 4: 11.

Published online 2014 Jun 1. doi: 10.1186/2044-5040-4-11

PMCID: PMC4067060

PMID: 24959344

(2014 katsaus)

Vandana A Gupta¹ and Alan H Beggs¹

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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.

Keywords: Kelch, BTB, BACK, Nemaline myopathy, Dystrophy, Congenital myopathy, Cul3, Ubiquitination, Proteasome, Skeletal muscle, Proliferation, Differentiation

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Review

Skeletal muscle development is a highly coordinated process that involves the myogenesis and differentiation of primary myoblasts, and their integrated growth and development into a mature functional organ [1-4]. Consequently, mutations of a large number of proteins associated with development and/or maintenance of skeletal muscle result in disease states. Over the past three decades, tremendous progress has been made in elucidating the genetic basis of muscle diseases. Primary inherited diseases of skeletal muscle include the muscular dystrophies and the non-dystrophic congenital myopathies [5-8].
 Muscular dystrophies are characterized by myofiber degeneration with repeated rounds of regeneration that ultimately lead to an end-stage process typified by fibrosis and replacement by adipose tissue [9,10].
In contrast, non-dystrophic myopathies exhibit little necrotic or regenerative changes, but muscle biopsies often display characteristic structural changes such as central cores, nemaline rods, central nuclei, various intracytoplasmic inclusions, or fiber type disproportion, and so on [10,11]. Collectively, these diseases are both phenotypically and clinically heterogeneous.

 
Gene discovery in muscle diseases is currently skyrocketing due to the use of next-generation sequencing approaches [12-19]. The discovery of new genes is not only crucial for improving diagnostics for these highly heterogeneous muscular disorders, but also is critical for identifying new molecular pathways that may serve as potential therapeutic targets. Recent gene discoveries have identified mutations in Kelch protein genes as the cause of muscle diseases in humans [14,20-22]. 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]. Kelch family members are involved in a number of cellular and molecular processes such as cell migration, cytoskeletal arrangement, regulation of cell morphology, protein degradation, and gene expression [25-31]. This review summarizes our emerging understanding of the various roles of Kelch proteins in skeletal muscle development and disease (Tables  1 and ​and22).

Table 1

Kelch family proteins in skeletal muscle development

Gene	Protein	Function	Expression
KLHL19	KLHL19, KEAP1	Oxidative stress and insulin signaling in muscle cells [32]	Ubiquitous [33]
KLHL31	KLHL31	Skeletal and cardiac muscle myogenesis [29,34]	Skeletal muscle, heart (low levels in brain, kidney, and liver) [29]
KLHL39	KLHL39, IVNS1ABP	Protection against drug-induced cardiomyopathy [35]	Ubiquitous [36]
KLHL40 (KBTBD5)	KLHL40	Skeletal muscle differentiation [14,37]	Skeletal muscle [14]
KLHL41 (KBTBD10 , KRP1)	KLHL41, Sarcosin	Skeletal muscle differentiation and myofibril assembly [22,38,39]	Skeletal muscle, lungs [22]
MKLN1	MKLN1, Muskelin	Muscle cell adhesion and extracellular communication [40]	Skeletal muscle, brain [40,41]
KLHDC1	KLHDC1	Muscle cell migration and differentiation [42,43]	Skeletal muscle [42]
KLHDC2	KLHDC2	Muscle cell migration and differentiation [42,43]	Skeletal muscle [42]

Table 2

Kelch family proteins in human diseases

Gene	Function	Expression
Neuromuscular diseases
KLHL1	Spinocerebellar ataxia type 8 [44]	Brain, prostate, small intestine, colon [44]
KLHL9	Distal myopathy [20]	Ubiquitous [20]
KLHL16 (GAN)	Giant axonal neuropathy [45]	Brain, skeletal muscle, heart, kidney, liver [46]
KLHL40 (KBTBD5)	Severe nemaline myopathy with fetal akinesia [14,37]	Skeletal muscle [14]
KLHL41 (KBTBD10)	Nemaline myopathy [22,38,39]	Skeletal muscle, lungs [22]
KBTBD13	Nemaline myopathy with cores [21]	Skeletal muscle, lungs, heart [21]
Cancer
KLHL6	Chronic lymphocytic leukemia [47]	Lymphocytes (unknown in other tissues) [48]
KLHL19 (KEAP1)	Pulmonary papillary adenocarcinoma [49]	Ubiquitous [50]
KLHL20	Prostate cancer progression [51]	Ubiquitous [52]
KLHL37 (ENC1)	Brain tumors [53]	Brain (unknown in other tissues) [54]
KLHDC8B	Hodgkin’s lymphoma [55]	Unknown

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Skelet Muscle. 2014; 4: 11. Published online 2014 Jun 1. doi: 10.1186/2044-5040-4-11 Copyright/LicenseRequest permission to reuse