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Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific-adapters for CUL3 E3 ubiquitin ligase to regulate protein turn-over through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM, however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric protein contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
This article was published in the following journal.
Name: Human molecular genetics
Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness, fiber atrophy and presence of nemaline bodies within myofibers. However, the understanding of underlying path...
To expand the clinical and genetic spectrum of nemaline myopathy 10 by a series of Austrian and German patients with a milder disease course and missense mutations in .
Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different g...
Amish nemaline myopathy (ANM) is a severe congenital form of NM, known to be fatal in early childhood due to pulmonary insufficiency. Homozygous mutations in TNNT1 were originally ascertained in an Ol...
The abundance of any protein is determined by the balance of protein synthesis and protein degradation. Regulated protein degradation has emerged as a powerful means of precisely controlling individua...
Nemaline myopathy is a rare congenital myopathy. Respiratory failure is the main cause of death in these patients. The primary objective of this study is to determine the effect of a 8-wee...
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Multiprotein complexes that mediate the activation of CASPASE-1. Dysregulation of inflammasomes has also been linked to a number of autoinflammatory and autoimmune disorders.
A group of inherited congenital myopathic conditions characterized clinically by weakness, hypotonia, and prominent hypoplasia of proximal muscles including the face. Muscle biopsy reveals large numbers of rod-shaped structures beneath the muscle fiber plasma membrane. This disorder is genetically heterogeneous and may occasionally present in adults. (Adams et al., Principles of Neurology, 6th ed, p1453)
Catalyzes the oxidation of catechol to 2-hydroxymuconate semialdehyde in the carbazole and BENZOATE degradation via HYDROXYLATION pathways. It also catalyzes the conversion of 3-methylcatechol to cis, cis-2-hydroxy-6-oxohept-2,4-dienoate in the TOLUENE and XYLENE degradation pathway. This enzyme was formerly characterized as EC 18.104.22.168.
The development and application of computational models of human pathophysiology that are individualized to patient-specific data.
A degradation process whereby incorrectly folded proteins are selectively transported out of the ENDOPLASMIC RETICULUM and into the CYTOSOL. The misfolded proteins are subsequently ubiquitinated and degraded by the PROTEASOME.
Congenital conditions are those which are present from birth. They include structural deformities or loss of function in organs such as the <!--LGfEGNT2Lhm-->heart, gut or skeletal system. They can be corrected by <!--LGfEGNT2Lhm-->surgery, m...
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