PUBLICATION
Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in Nemaline Myopathy
- Authors
- Jirka, C., Pak, J.H., Grosgogeat, C.A., Marchetii, M.M., Gupta, V.A.
- ID
- ZDB-PUB-190416-20
- Date
- 2019
- Source
- Human molecular genetics 28(15): 2549-2560 (Journal)
- Registered Authors
- Gupta, Vandana A
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cytoskeletal Proteins/metabolism*
- Disease Models, Animal
- Gene Knockout Techniques
- Mice
- Muscle Proteins/metabolism*
- Muscle, Skeletal/metabolism*
- Myofibrils/metabolism
- Myopathies, Nemaline/genetics
- Myopathies, Nemaline/metabolism*
- Myopathies, Nemaline/physiopathology
- Phenotype
- Proteasome Endopeptidase Complex/metabolism
- Proteolysis
- Ubiquitination*
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 30986853 Full text @ Hum. Mol. Genet.
Citation
Jirka, C., Pak, J.H., Grosgogeat, C.A., Marchetii, M.M., Gupta, V.A. (2019) Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in Nemaline Myopathy. Human molecular genetics. 28(15):2549-2560.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping