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

作者：Silvio Alessandro Di Gioia, Samantha Connors, Norisada Matsunami, Jessica Cannavino, Matthew F. Rose, Nicole M. Gilette, Pietro Artoni, Nara Sobreira, Wai‐Man Chan, Bryn D. Webb, Caroline D. Robson, Long Cheng, Carol Van Ryzin, Andres Ramirez-Martinez, Payam Mohassel, Mark Leppert, Mary Beth Scholand, Christopher Grunseich, Carlos R. Ferreira, Tyler Hartman, Ian Hayes, Tim Morgan, David Markie, Michela Fagiolini, Amy J. Swift, Peter S. Chines, Carlos E. Speck‐Martins, Francis S. Collins, Ethylin Wang Jabs, Carsten G. Bönnemann, Eric N. Olson, Caroline Andrews, Brenda J. Barry, David G. Hunter, Sarah MacKinnon, Sherin Shaaban, Mónica Erazo, Tamiesha Frempong, Ke Hao, Thomas P. Naidich, Janet C. Rucker, Zhongyang Zhang, Barbara B. Biesecker, Lori L. Bonnycastle, Carmen C. Brewer, Brian P. Brooks, John A. Butman, Wade W. Chien, Kathleen Farrell, Edmond J. FitzGibbon, Andrea Gropman, Elizabeth Hutchinson, Minal S. Jain, Kelly King, Tanya Lehky, Janice Lee, Denise K. Liberton, Narisu Narisu, Scott M. Paul, Neda Sadeghi, Joseph Snow, Beth Solomon, Angela C. Summers, Camilo Toro, Audrey Thurm, Christopher Zalewski, John C. Carey, Stephen P. Robertson, Irini Manoli, Elizabeth C. Engle · 发表于：Nature Communications · 年份：2017 · DOI：10.1038/ncomms16077 · 被引用次数：112 · 研究领域：Genomics and Rare Diseases、Neurogenetic and Muscular Disorders Research、Muscle Physiology and Disorders

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 mymk insT/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.