Genetic analysis of VCP and WASH-complex genes in a German cohort of sporadic ALS-FTD patients

Publication date: Available online 3 May 2017
Source:Neurobiology of Aging
Author(s): Matthias Türk, Rolf Schröder, Katharina Khuller, Andreas Hofmann, Carolin Berwanger, Albert C. Ludolph, Gabriele Dekomien, Kathrin Müller, Jochen H. Weishaupt, Christian T. Thiel, Christoph S. Clemen
Mutations of the human VCP and WASH complex genes cause motor neuron and cognitive impairment disorders. Here, we analyzed a cohort of German patients with sporadic amyotrophic lateral sclerosis and frontotemporal lobar degeneration co-morbidity (ALS/FTD) for VCP and WASH complex gene mutations. Next generation panel sequencing of VCP, WASH1, FAM21C, CCDC53, SWIP, strumpellin, CAPZA1 and CAPZB genes was performed in 43 sporadic ALS/FTD patients. Subsequent analyses included Sanger sequencing, in silico analyses, real-time PCR, and CCDC53 immunoblotting. We identified one patient with the heterozygous variant c.26C>T in CAPZA1, predicted to result in p.Ser9Leu, and a second with the heterozygous start codon variant c.2T>C in CCDC53. In silico analysis predicted structural changes in the N-terminus of CAPZα1, which may interfere with the CAPZα:CAPZβ dimerization. Though the translation initiation codon of CCDC53 is mutated, real-time PCR and immunoblotting did neither reveal any evidence for a CCDC53 haploinsufficiency nor for aberrant CCDC53 protein species. Moreover, a disease-causing C9orf72 repeat expansion mutation was later on identified in this patient. Thus, with exception of a putatively pathogenic heterozygous c.26C>T CAPZA1 variant, our genetic analysis did not reveal mutations in VCP and the remaining WASH complex subunits.



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