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Dis Model Mech. 2017 Feb 1;10(2):105-118. doi: 10.1242/dmm.026476. Epub 2016 Dec 15.

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

Author information

1
Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
2
The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
3
Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
4
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
5
Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany.
6
Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore.
7
Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore.
8
Singapore Institute for Clinical Sciences, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 117609, Singapore.
9
Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan.
10
Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
11
Department of Molecular Developmental Biology, Radboud University, Nijmegen 6525GA, The Netherlands.
12
Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine (ICMM), The Panum Institute, University of Copenhagen, Copenhagen 2200, Denmark.
13
Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Bispebjerg Hospital/Rigshospitalet, Copenhagen 2400, Denmark.
14
Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup 2600, Denmark.
15
National Institute of Rehabilitation Medicine (NIRM), Islamabad 44000, Pakistan.
16
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium.
17
Department of Neurology, Antwerp University Hospital, Antwerp 2000, Belgium.
18
Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp 2000, Belgium.
19
Department of Neurology, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
20
Singapore Eye Research Institute, Singapore 168751, Singapore.
21
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 168751, Singapore.
22
COMSATS Institute of Information Technology, Islamabad 45550, Pakistan.
23
Al-Nafees Medical College & Hospital, Isra University, Islamabad 45600, Pakistan.

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.

KEYWORDS:

Drosophila; Dystonia; FITM2; Hearing impairment; Lipid droplets; Motor development

PMID:
28067622
PMCID:
PMC5312003
DOI:
10.1242/dmm.026476
[Indexed for MEDLINE]
Free PMC Article

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