Abstract
ABSTRACTA 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.
Highlights
Hearing involves the transformation of sounds into electrical signals by the inner ear and the subsequent processing of these signals along the central auditory pathways
Significant dystonic limb movements were present in three cases and truncal dystonia was observed in individuals II:5 and II:8
Downregulation of Fitm causes abnormal dendrite branching and field coverage of Drosophila multi-dendritic sensory neurons As signs of a sensory neuropathy are part of the syndrome caused by a nonsense mutation in FITM2, we evaluated the role of Fitm in sensory neuron development by inspecting the dorsal class IV dendritic arborization C neurons in third instar larvae
Summary
Hearing involves the transformation of sounds into electrical signals by the inner ear and the subsequent processing of these signals along the central auditory pathways. Mutations in over a hundred genes cause auditory malfunction and hearing impairment (http:// hereditaryhearingloss.org/). Defects in the proteins that function in the inner ear can give rise to hearing impairment only (nonsyndromic) or, as the function of implicated proteins is often not limited to the auditory system, they can result in multisystem disorders (syndromic hearing impairment). For some of the cases with a causative mutation identified, disruption of energy homeostasis and/or metabolism are emerging as a common theme. This is true for Mohr–Tranebjaerg syndrome (MIM# 304700, http://www.ncbi.nlm.nih.gov/omim) with mutations in TIMM8A (MIM# 300356) (Jin et al, 1996), and for a number of rare mitochondrial disorders with mutations in mitochondrial genes as well as for SUCLA2-associated disease (MIM #612073) (Carrozzo et al, 2007)
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