A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome
نویسندگان
چکیده
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.
منابع مشابه
Carey-Fineman-Ziter (CFZ) syndrome: report on affected sibs.
We describe a sib pair with craniofacial anomalies, micrognathia, Mobius sequence, generalised myopathy, relative macrocephaly, and developmental delay. They appear to have the Carey-Fineman-Ziter syndrome (MIM 254940), which has been reported in only four children, a sib pair and two sporadic cases. This report on an additional affected brother and sister pair supports autosomal inheritance as...
متن کاملWhole-exome sequencing identifies mutations in MYMK in a mild form of Carey-Fineman-Ziter syndrome
Fusion of single-nucleated myoblasts is essential for the formation of multinucleated myocytes. Mechanisms that regulate myoblast fusion have been a focus of recent studies. Transmembrane protein 8 (TMEM8C), also known as myomaker, is a highly conserved muscle-specific transmembrane protein encoded by the MYMK gene. The protein is expressed during early muscle development. Mymk-null mice die so...
متن کاملPontine hypoplasia in Carey-Fineman-Ziter (CFZ) syndrome.
We describe an infant with multiple congenital anomalies including cleft palate and micrognathia, Möbius sequence, developmental delay, myopathy, hydronephrosis, and bilateral clubfeet. These features are consistent with Carey-Fineman-Ziter (CFZ) syndrome (MIM 254940), which has been previously reported in six children (including two sibling pairs). Cranial magnetic resonance imaging (MRI) reve...
متن کاملSevere congenital myopathy with Möbius, Robin, and Poland sequences: new aspects of the Carey-Fineman-Ziter syndrome.
We report a boy with severe congenital myopathy, Möbius-Poland sequence, Robin sequence, and severe developmental delay. We consider this patient to have Carey-Fineman-Ziter syndrome. Since this is only the seventh case reported, this case helps to define further the consistent manifestations of this recognizable phenotype. Additionally our patient shows laryngostenosis, intermittent episodes o...
متن کاملFHL1 Reduces Dystrophy in Transgenic Mice Overexpressing FSHD Muscular Dystrophy Region Gene 1 (FRG1)
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differen...
متن کامل