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A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.

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.

SUBMITTER: Zazo Seco C

PROVIDER: S-EPMC5312003 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.

Zazo Seco Celia C Castells-Nobau Anna A Joo Seol-Hee SH Schraders Margit M Foo Jia Nee JN van der Voet Monique M Velan S Sendhil SS Nijhof Bonnie B Oostrik Jaap J de Vrieze Erik E Katana Radoslaw R Mansoor Atika A Huynen Martijn M Szklarczyk Radek R Oti Martin M Tranebjærg Lisbeth L van Wijk Erwin E Scheffer-de Gooyert Jolanda M JM Siddique Saadat S Baets Jonathan J de Jonghe Peter P Kazmi Syed Ali Raza SA Sadananthan Suresh Anand SA van de Warrenburg Bart P BP Khor Chiea Chuen CC Göpfert Martin C MC Qamar Raheel R Schenck Annette A Kremer Hannie H Siddiqi Saima S

Disease models & mechanisms 20161215 2

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 d ...[more]

PMID: 28067622

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Project description:BackgroundE-52862 (S1RA, 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]-morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E-52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.MethodsMechanical and thermal response thresholds were tested on 7-, 13-, 14- and 15-week-old ZDF rats treated with saline or with E-52862 acutely administered on week 13, followed by sub-chronic administration (14 days). Axonal peripheral activity (skin-saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15-week-old ZDF rats treated with saline or E-52862 and in LEAN rats.ResultsZucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single-dose and sub-chronic E-52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E-52862 treatment increased the mean mechanical threshold (77.3 ± 21 mN vs. 19.6 ± 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 ± 36.5 vs. 352.8 ± 41.4 spikes) or by repeated mechanical supra-threshold steps (39.4 ± 1.4 vs. 83.5 ± 0.9). E-52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed.ConclusionsE-52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat.SignificanceBlockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients. WHAT DOES THIS STUDY ADD?: This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats. The methodology includes behavioural evidences, electrophysiological data and vascular-isolated models.

Dataset Information

A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.

Publications

A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.

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