Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice

James B. Papizan, Glynnis A. Garry, Svetlana Brezprozvannaya, John R. McAnally, Rhonda Bassel-Duby, Ning Liu, Eric N. Olson

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substratespecific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2. To explore its functions in vivo, we created a mouse model of Klhl31 loss of function using the CRISPR-Cas9 system. Mice lacking Klhl31 exhibited stunted postnatal skeletal muscle growth, centronuclear myopathy, central cores, Z-disc streaming, and SR dilation. We used proteomics to identify several candidate Klhl31 substrates, including Filamin-C (FlnC). In the Klhl31-knockout mice, FlnC protein levels were highly upregulated with no change in transcription, and we further demonstrated that Klhl31 targets FlnC for ubiquitination and degradation. These findings highlight a role for Klhl31 in the maintenance of skeletal muscle structure and provide insight into the mechanisms underlying congenital myopathies.

Original languageEnglish (US)
Pages (from-to)3730-3740
Number of pages11
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

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Filamins
Myotonia Congenita
Sarcomeres
Ubiquitination
Sarcoplasmic Reticulum
Skeletal Muscle
Clustered Regularly Interspaced Short Palindromic Repeats
Congenital Structural Myopathies
MEF2 Transcription Factors
Maintenance
Contractile Proteins
Muscles
Proteins
Protein Stability
Knockout Mice
Proteomics
Dilatation
Calcium
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice. / Papizan, James B.; Garry, Glynnis A.; Brezprozvannaya, Svetlana; McAnally, John R.; Bassel-Duby, Rhonda; Liu, Ning; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 127, No. 10, 02.10.2017, p. 3730-3740.

Research output: Contribution to journalArticle

Papizan, James B. ; Garry, Glynnis A. ; Brezprozvannaya, Svetlana ; McAnally, John R. ; Bassel-Duby, Rhonda ; Liu, Ning ; Olson, Eric N. / Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 10. pp. 3730-3740.
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