A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Abstract

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

Acting on identity: Myoblast fusion and the formation of the syncytial muscle fiber

“…Myomaker is a transmembrane protein that is specifically expressed in the muscles during muscle development and regeneration (Landemaine et al, 2014; Luo et al, 2015; Millay et al, 2013; 2014; Zhang and Roy, 2017). In humans, reduced Myomaker function is linked to Carey-Fineman-Ziter syndrome (Di Gioia et al, 2017), a congenital myopathy. Myomaker is required for fusion and is localized to the adhesion site.…”

Trout myomaker contains 14 minisatellites and two sequence extensions but retains fusogenic function

“…Another muscle-specific transmembrane protein of 221 aa, 2 called myomaker, was found to be necessary for myocyte fusion during mouse embryonic development (9) and muscle regeneration (10). In humans, the loss of myomaker activity can lead to disease (11). In vitro, mouse myomaker drives heterologous fusion between fibroblasts and myoblasts, but not between fibroblasts (9).…”

240th ENMC workshop: The involvement of skeletal muscle stem cells in the pathology of muscular dystrophies 25–27 January 2019, Hoofddorp, The Netherlands

“…This syndrome was originally described in two siblings with bilateral facial weakness and Robin sequence (mandibular hypoplasia, hypoglossia, cleft palate), as well as mild proximal weakness with small muscles, delayed motor milestones, scoliosis, and normal intelligence. As part of an investigation into genetic causes for Moebius syndrome biallelic mutations in the gene myomaker/ TMEM8C were identified in the original family as well as in four additional families with a total of 8 patients [6] . The clinical phenotype was fairly consistent with prominent congenital bifacial weakness but without prominent ophthalmoplegia, prominent axial weakness and milder involvement of extremity muscles.…”

“…Mutations in genes that regulate satellite cell/myoblast activity are implicated in some congenital muscular dystrophies [6,7] . Here, altered behaviour of myoblasts prior to them fusing to form myofibres during embryogenesis and early growth results in impaired muscle formation evident at birth.…”