MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis

Kyungsoo Ha, Jillian G. Buchan, David M. Alvarado, Kevin Mccall, Anupama Vydyanath, Pradeep K. Luther, Matthew I. Goldsmith, Matthew B. Dobbs, Christina A. Gurnett

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.

Original languageEnglish
Article numberddt344
Pages (from-to)4967-4977
Number of pages11
JournalHuman molecular genetics
Volume22
Issue number24
DOIs
StatePublished - Dec 2013

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