期刊
DISEASE MODELS & MECHANISMS
卷 10, 期 2, 页码 105-118出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dmm.026476
关键词
FITM2; Lipid droplets; Drosophila; Hearing impairment; Motor development; Dystonia
资金
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) [91-614-084, 433-09-229, 917-96-346]
- ZonMw TOP subsidies [912-12-109, 40-00812-98-09047]
- Deutsche Forschungsgemeinschaft [GO 1092/2, SPP 1680, SFB 889 A1, INST 186/1081-1]
- Higher Education Commission, Pakistan
- Association Belge contre les Maladies Neuro-Musculaires
- European Union [2012-305121]
- Fonds Wetenschappelijk Onderzoek
- National Research Program for Universities [4885]
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.
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