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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

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

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.

TidsskriftDisease models & mechanisms
Sider (fra-til)105-118
Antal sider14
StatusUdgivet - feb. 2017

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