Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis. Issue 8 (5th May 2019)

• Record Type: Journal Article
• Authors: Shashi, Vandana; Geist, Janelle; Lee, Youngha; Yoo, Yongjin; Shin, Unbeom; Schoch, Kelly; Sullivan, Jennifer; Stong, Nicholas; Smith, Edward; Jasien, Joan; Kranz, Peter; Lee, Yoonsung; Shin, Yong Beom; Wright, Nathan T.; Choi, Murim; Kontrogianni‐Konstantopoulos, Aikaterini
• Other Names: Acosta Maria T. investigator.; Adams David R. investigator.; Aday Aaron investigator.; Alejandro Mercedes E. investigator.; Allard Patrick investigator.; Ashley Euan A. investigator.; Azamian Mahshid S. investigator.; Bacino Carlos A. investigator.; Bademci Guney investigator.; Baker Eva investigator.; Balasubramanyam Ashok investigator.; Baldridge Dustin investigator.; Barbouth Deborah investigator.; Batzli Gabriel F. investigator.; Beggs Alan H. investigator.; Bellen Hugo J. investigator.; Bernstein Jonathan A. investigator.; Berry Gerard T. investigator.; Bican Anna investigator.; Bick David P. investigator.; Birch Camille L. investigator.; Bivona Stephanie investigator.; Bonnenmann Carsten investigator.; Bonner Devon investigator.; Boone Braden E. investigator.; Bostwick Bret L. investigator.; Briere Lauren C. investigator.; Brokamp Elly investigator.; Brown Donna M. investigator.; Brush Matthew investigator.; Burke Elizabeth A. investigator.; Burrage Lindsay C. investigator.; Butte Manish J. investigator.; Carrasquillo Olveen investigator.; Chang Ta Chen Peter investigator.; Chao Hsiao‐Tuan investigator.; Clark Gary D. investigator.; Coakley Terra R. investigator.; Cobban Laurel A. investigator.; Cogan Joy D. investigator.; Cole F. Sessions investigator.; Colley Heather A. investigator.; Cooper Cynthia M. investigator.; Cope Heidi investigator.; Craigen William J. investigator.; D'Souza Precilla investigator.; Dasari Surendra investigator.; Davids Mariska investigator.; Davidson Jean M. investigator.; Dayal Jyoti G. investigator.; Dell'Angelica Esteban C. investigator.; Dhar Shweta U. investigator.; Dorrani Naghmeh investigator.; Dorset Daniel C. investigator.; Douine Emilie D. investigator.; Draper David D. investigator.; Dries Annika M. investigator.; Duncan Laura investigator.; Eckstein David J. investigator.; Emrick Lisa T. investigator.; Eng Christine M. investigator.; Enns Gregory M. investigator.; Esteves Cecilia investigator.; Estwick Tyra investigator.; Fernandez Liliana investigator.; Ferreira Carlos investigator.; Fieg Elizabeth L. investigator.; Fisher Paul G. investigator.; Fogel Brent L. investigator.; Forghani Irman investigator.; Friedman Noah D. investigator.; Gahl William A. investigator.; Godfrey Rena A. investigator.; Goldman Alica M. investigator.; Goldstein David B. investigator.; Gourdine Jean‐Philippe F. investigator.; Grajewski Alana investigator.; Groden Catherine A. investigator.; Gropman Andrea L. investigator.; Haendel Melissa investigator.; Hamid Rizwan investigator.; Hanchard Neil A. investigator.; High Frances investigator.; Holm Ingrid A. investigator.; Hom Jason investigator.; Huang Alden investigator.; Huang Yong investigator.; Isasi Rosario investigator.; Jamal Fariha investigator.; Jiang Yong‐hui investigator.; Johnston Jean M. investigator.; Jones Angela L. investigator.; Karaviti Lefkothea investigator.; Kelley Emily G. investigator.; Koeller David M. investigator.; Kohane Isaac S. investigator.; Kohler Jennefer N. investigator.; Krakow Deborah investigator.; Krasnewich Donna M. investigator.; Korrick Susan investigator.; Koziura Mary investigator.; Krier Joel B. investigator.; Kyle Jennifer E. investigator.; Lalani Seema R. investigator.; Lam Byron investigator.; Lanpher Brendan C. investigator.; Lanza Ian R. investigator.; Lau C. Christopher investigator.; Lazar Jozef investigator.; LeBlanc Kimberly investigator.; Lee Brendan H. investigator.; Lee Hane investigator.; Levitt Roy investigator.; Levy Shawn E. investigator.; Lewis Richard A. investigator.; Lincoln Sharyn A. investigator.; Liu Pengfei investigator.; Liu Xue Zhong investigator.; Loo Sandra K. investigator.; Loscalzo Joseph investigator.; Maas Richard L. investigator.; Macnamara Ellen F. investigator.; MacRae Calum A. investigator.; Maduro Valerie V. investigator.; Majcherska Marta M. investigator.; Malicdan May Christine V. investigator.; Mamounas Laura A. investigator.; Manolio Teri A. investigator.; Markello Thomas C. investigator.; Marom Ronit investigator.; Martin Martin G. investigator.; Martínez‐Agosto Julian A. investigator.; Marwaha Shruti investigator.; May Thomas investigator.; McCauley Jacob investigator.; McConkie‐Rosell Allyn investigator.; McCormack Colleen E. investigator.; McCray Alexa T. investigator.; Merker Jason D. investigator.; Metz Thomas O. investigator.; Might Matthew investigator.; Morava‐Kozicz Eva investigator.; Moretti Paolo M. investigator.; Morimoto Marie investigator.; Mulvihill John J. investigator.; Murdock David R. investigator.; Nath Avi investigator.; Nelson Stan F. investigator.; Newberry J. Scott investigator.; Newman John H. investigator.; Nicholas Sarah K. investigator.; Novacic Donna investigator.; Oglesbee Devin investigator.; Orengo James P. investigator.; Pak Stephen investigator.; Pallais J. Carl investigator.; Palmer Christina GS. investigator.; Papp Jeanette C. investigator.; Parker Neil H. investigator.; Pena Loren DM. investigator.; Phillips John A. investigator.; Posey Jennifer E. investigator.; Postlethwait John H. investigator.; Potocki Lorraine investigator.; Pusey Barbara N. investigator.; Renteria Genecee investigator.; Reuter Chloe M. investigator.; Rives Lynette investigator.; Robertson Amy K. investigator.; Rodan Lance H. investigator.; Rosenfeld Jill A. investigator.; Rowley Robb K. investigator.; Sacco Ralph investigator.; Sampson Jacinda B. investigator.; Samson Susan L. investigator.; Saporta Mario investigator.; Schaechter Judy investigator.; Schedl Timothy investigator.; Schoch Kelly investigator.; Scott Daryl A. investigator.; Shakachite Lisa investigator.; Sharma Prashant investigator.; Shashi Vandana investigator.; Shields Kathleen investigator.; Shin Jimann investigator.; Signer Rebecca investigator.; Sillari Catherine H. investigator.; Silverman Edwin K. investigator.; Sinsheimer Janet S. investigator.; Smith Kevin S. investigator.; Solnica‐Krezel Lilianna investigator.; Spillmann Rebecca C. investigator.; Stoler Joan M. investigator.; Stong Nicholas investigator.; Sullivan Jennifer A. investigator.; Sweetser David A. investigator.; Tamburro Cecelia P. investigator.; Tan Queenie K.‐G. investigator.; Tekin Mustafa investigator.; Telischi Fred investigator.; Thorson Willa investigator.; Tifft Cynthia J. investigator.; Toro Camilo investigator.; Tran Alyssa A. investigator.; Urv Tiina K. investigator.; Vogel Tiphanie P. investigator.; Waggott Daryl M. investigator.; Wahl Colleen E. investigator.; Walley Nicole M. investigator.; Walsh Chris A. investigator.; Walker Melissa investigator.; Wambach Jennifer investigator.; Wan Jijun investigator.; Wang Lee‐kai investigator.; Wangler Michael F. investigator.; Ward Patricia A. investigator.; Waters Katrina M. investigator.; Webb‐Robertson Bobbie‐Jo M. investigator.; Wegner Daniel investigator.; Westerfield Monte investigator.; Wheeler Matthew T. investigator.; Wise Anastasia L. investigator.; Wolfe Lynne A. investigator.; Woods Jeremy D. investigator.; Worthey Elizabeth A. investigator.; Yamamoto Shinya investigator.; Yang John investigator.; Yoon Amanda J. investigator.; Yu Guoyun investigator.; Zastrow Diane B. investigator.; Zhao Chunli investigator.; Zuchner Stephan investigator.;
• Is Part Of: Human mutation. Volume 40:Issue 8(2019)
• Page Start: 1115
• Page End: 1126
• Publication Date: 2019-05-05
• Subjects: arthrogryposis -- hypotonia -- MYBPC1 -- myopathy -- myosin binding protein‐C -- tremor; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23760
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Encoding the slow skeletal muscle isoform of myosin binding protein‐C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M‐motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M‐motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M‐motif to myosin, which likely impairs the formation of actomyosin cross‐bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early‐onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.