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

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


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.

MeSH terms

  • Adiposity
  • Animals
  • Audiometry, Pure-Tone
  • Base Sequence
  • Child
  • Codon, Nonsense / genetics
  • Deaf-Blind Disorders / blood
  • Deaf-Blind Disorders / genetics*
  • Deaf-Blind Disorders / physiopathology
  • Disease Models, Animal
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Dystonia / blood
  • Dystonia / genetics*
  • Dystonia / physiopathology
  • Exome Sequencing
  • Female
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Hearing Loss / genetics
  • Homozygote
  • Humans
  • Ichthyosis / complications
  • Ichthyosis / genetics*
  • Ichthyosis / physiopathology
  • Intellectual Disability / blood
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Lipid Droplets / metabolism
  • Liver / metabolism
  • Locomotion
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Motor Activity*
  • Mutation / genetics*
  • Optic Atrophy / blood
  • Optic Atrophy / genetics*
  • Optic Atrophy / physiopathology
  • Pedigree
  • Sensory Receptor Cells / pathology*
  • Young Adult


  • Codon, Nonsense
  • Drosophila Proteins
  • FITM2 protein, human
  • Membrane Proteins

Supplementary concepts

  • Mohr-Tranebjaerg syndrome