학술논문
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy
Document Type
Article
Author
Zazo Seco, Celia; Castells-Nobau, Anna; Joo, Seol-hee; Schraders, Margit; Foo, Jia Nee; van der Voet, Monique; Velan, S. Sendhil; Nijhof, Bonnie; Oostrik, Jaap; de Vrieze, Erik; Katana, Radoslaw; Mansoor, Atika; Huynen, Martijn; Szklarczyk, Radek; Oti, Martin; Tranebjærg, Lisbeth; van Wijk, Erwin; Scheffer-de Gooyert, Jolanda M.; Siddique, Saadat; Baets, Jonathan; de Jonghe, Peter; Kazmi, Syed Ali Raza; Sadananthan, Suresh Anand; van de Warrenburg, Bart P.; Khor, Chiea Chuen; Göpfert, Martin C.; Qamar, Raheel; Schenck, Annette; Kremer, Hannie; Siddiqi, Saima
Source
Disease Models and Mechanisms; February 2017, Vol. 10 Issue: 2 p105-118, 14p
Subject
Language
ISSN
17548403; 17548411
Abstract
A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*), in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.