Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Abstract

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.

• Authors: M Brigita Tan-Sindhunata, Inge B Mathijssen, Margriet Smit, Frank Baas, Johanna I de Vries, J Patrick van der Voorn, Irma Kluijt, Marleen A Hagen, Eveline W Blom, Erik Sistermans, Hanne Meijers-Heijboer, Quinten Waisfisz, Marjan M Weiss, Alexander J Groffen
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 23 Issue 9 Pg. 1151-7 (Sep 2015) ISSN: 1476-5438 [Electronic] England
• PMID: 25537362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cholinergic
• MUSK protein, human
• Receptor Protein-Tyrosine Kinases

Topics

• Alleles
• Amino Acid Sequence
• Arthrogryposis (diagnosis, genetics, pathology)
• Base Sequence
• Female
• Fetus
• Founder Effect
• Gene Expression
• Gene Frequency
• Genes, Lethal
• Genetic Testing
• Homozygote
• Humans
• Male
• Molecular Sequence Data
• Motor Endplate (genetics, pathology)
• Muscle Cells (metabolism, pathology)
• Mutation
• Netherlands
• Pedigree
• Prenatal Diagnosis
• Primary Cell Culture
• Receptor Protein-Tyrosine Kinases (genetics)
• Receptors, Cholinergic (chemistry, genetics)