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.
Highlights
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation
We demonstrate that recessive mutations in MYMK cause Carey-Fineman-Ziter syndrome in humans (CFZS) through a combination of one hypomorphic and one null allele, or two hypomorphic alleles, which reduce MYMK function and myoblast fusion below a threshold but not to zero (Supplementary Fig. 4)
It will be of interest to identify and phenotype individuals who are homozygous for the M1 or compound heterozygous for the M1 and M5 alleles to define the threshold of MYMK activity below which one manifests the CFZS phenotype
Summary
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. 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 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. Heterologous cell fusion assays and zebrafish modelling demonstrate that MYMK mutations cause CFZS by reducing but not eliminating MYMK function
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