TY - JOUR
T1 - Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.
AU - Tan-Sindhunata, M.B.
AU - Matthijssen, I.B.
AU - Smit, M.
AU - Baas, F.
AU - de Vries, J.I.P.
AU - van der Voorn, J.P.
AU - Kluijt, I.
AU - Hagen, M.A.
AU - Blom, E.W.
AU - Sistermans, E.A.
AU - Heijboer-Meijers, J.E.
AU - Waisfisz, Q.
AU - Weiss, M.M.
AU - Groffen, A.J.A.
AU - Mathijssen, Inge B.
N1 - Funding Information: We are grateful to the families for their cooperation. We thank Bertus Kuyt and Loes Stoets for the genealogy data, Alessandra Maugeri for helping with the Sanger sequencing analysis and Ruud Wolterman for tissue culture of primary myocytes. This work was financially supported by the Netherlands Genomics Initiative at the Centre for Medical Systems Biology (CMSB2) and the Netherlands Organization for Health Research and Development (ZonMW, project 91113022). Publisher Copyright: © 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/9/14
Y1 - 2015/9/14
N2 - Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.
AB - Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.
UR - http://www.scopus.com/inward/record.url?scp=84939261094&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ejhg.2014.273
DO - https://doi.org/10.1038/ejhg.2014.273
M3 - Article
C2 - 25537362
SN - 1018-4813
VL - 23
SP - 1151
EP - 1157
JO - European journal of human genetics
JF - European journal of human genetics
IS - 9
ER -
