KLHL40 deficiency destabilizes thin filament proteins and promotes Nemaline myopathy

Ankit Garg, Jason O'Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40(KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40 -/- mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients.

Original languageEnglish (US)
Pages (from-to)3529-3539
Number of pages11
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

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Nemaline Myopathies
Sarcomeres
Proteins
Myotonia Congenita
Muscles
Muscle Proteins
Ubiquitination
Skeletal Muscle

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., ... Olson, E. N. (2014). KLHL40 deficiency destabilizes thin filament proteins and promotes Nemaline myopathy. Journal of Clinical Investigation, 124(8), 3529-3539. https://doi.org/10.1172/JCI74994

KLHL40 deficiency destabilizes thin filament proteins and promotes Nemaline myopathy. / Garg, Ankit; O'Rourke, Jason; Long, Chengzu; Doering, Jonathan; Ravenscroft, Gianina; Bezprozvannaya, Svetlana; Nelson, Benjamin R.; Beetz, Nadine; Li, Lin; Chen, She; Laing, Nigel G.; Grange, Robert W.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3529-3539.

Research output: Contribution to journalArticle

Garg, A, O'Rourke, J, Long, C, Doering, J, Ravenscroft, G, Bezprozvannaya, S, Nelson, BR, Beetz, N, Li, L, Chen, S, Laing, NG, Grange, RW, Bassel-Duby, R & Olson, EN 2014, 'KLHL40 deficiency destabilizes thin filament proteins and promotes Nemaline myopathy', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3529-3539. https://doi.org/10.1172/JCI74994
Garg A, O'Rourke J, Long C, Doering J, Ravenscroft G, Bezprozvannaya S et al. KLHL40 deficiency destabilizes thin filament proteins and promotes Nemaline myopathy. Journal of Clinical Investigation. 2014 Aug 1;124(8):3529-3539. https://doi.org/10.1172/JCI74994
Garg, Ankit ; O'Rourke, Jason ; Long, Chengzu ; Doering, Jonathan ; Ravenscroft, Gianina ; Bezprozvannaya, Svetlana ; Nelson, Benjamin R. ; Beetz, Nadine ; Li, Lin ; Chen, She ; Laing, Nigel G. ; Grange, Robert W. ; Bassel-Duby, Rhonda ; Olson, Eric N. / KLHL40 deficiency destabilizes thin filament proteins and promotes Nemaline myopathy. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3529-3539.
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AU - Bezprozvannaya, Svetlana

AU - Nelson, Benjamin R.

AU - Beetz, Nadine

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AU - Bassel-Duby, Rhonda

AU - Olson, Eric N.

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