التفاصيل البيبلوغرافية
| العنوان: |
Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence. |
| المؤلفون: |
Tan-Sindhunata, M Brigita, Mathijssen, Inge B, Smit, Margriet, Baas, Frank, de Vries, Johanna I, van der Voorn, J Patrick, Kluijt, Irma, Hagen, Marleen A, Blom, Eveline W, Sistermans, Erik, Meijers-Heijboer, Hanne, Waisfisz, Quinten, Weiss, Marjan M, Groffen, Alexander J |
| المصدر: |
European Journal of Human Genetics; Sep2015, Vol. 23 Issue 9, p1151-1157, 7p |
| مصطلحات موضوعية: |
GENETIC testing, GENETIC disorders, GENETIC mutation, PROTEIN-tyrosine kinases, SYNAPTOGENESIS |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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