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.
PY - 2015
Y1 - 2015
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 - https://www.scopus.com/pages/publications/84939261094
UR - https://www.scopus.com/inward/citedby.url?scp=84939261094&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2014.273
DO - 10.1038/ejhg.2014.273
M3 - Article
SN - 1018-4813
VL - 23
SP - 1151
EP - 1157
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -
