A homozygousFITM2mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy | Zendy

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

Open Access

A homozygousFITM2mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

Author(s) -

Celia Zazo Seco,

Anna CastellsNobau,

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 A. Huynen,

Radek Szklarczyk,

Martin Oti,

Lisbeth Tranebjærg,

Erwin van Wijk,

Jolanda M. Scheffer-de Gooyert,

Saadat Siddique,

Jonathan Baets,

Peter De Jonghe,

Syed Ali Raza Kazmi,

Suresh Anand Sadananthan,

Bart P.C. van de Warrenburg,

Chiea Chuen Khor,

Martin C. Göpfert,

Raheel Qamar,

Annette Schenck,

Hannie Kremer,

Saima Siddiqi

Publication year - 2016

Publication title -

disease models and mechanisms

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.327

H-Index - 83

eISSN - 1754-8411

pISSN - 1754-8403

DOI - 10.1242/dmm.026476

Subject(s) - exome sequencing , genetics , biology , mutation , ichthyosis , nonsense mutation , dystonia , exome , genetic heterogeneity , neuroscience , phenotype , gene , missense mutation

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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