Disease Models & Mechanisms (Feb 2017)
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy
- 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,
- 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. van de Warrenburg,
- Chiea Chuen Khor,
- Martin C. Göpfert,
- Raheel Qamar,
- Annette Schenck,
- Hannie Kremer,
- Saima Siddiqi
Affiliations
- Celia Zazo Seco
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Anna Castells-Nobau
- Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Seol-hee Joo
- Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany
- Margit Schraders
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Jia Nee Foo
- Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore
- Monique van der Voet
- Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- S. Sendhil Velan
- Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore
- Bonnie Nijhof
- Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Jaap Oostrik
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Erik de Vrieze
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Radoslaw Katana
- Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany
- Atika Mansoor
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan
- Martijn Huynen
- Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Radek Szklarczyk
- Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Martin Oti
- The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Lisbeth Tranebjærg
- Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine (ICMM), The Panum Institute, University of Copenhagen, Copenhagen 2200, Denmark
- Erwin van Wijk
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Jolanda M. Scheffer-de Gooyert
- Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Saadat Siddique
- National Institute of Rehabilitation Medicine (NIRM), Islamabad 44000, Pakistan
- Jonathan Baets
- Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium
- Peter de Jonghe
- Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium
- Syed Ali Raza Kazmi
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan
- Suresh Anand Sadananthan
- Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore
- Bart P. van de Warrenburg
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Chiea Chuen Khor
- Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore
- Martin C. Göpfert
- Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany
- Raheel Qamar
- COMSATS Institute of Information Technology, Islamabad 45550, Pakistan
- Annette Schenck
- Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Hannie Kremer
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
- Saima Siddiqi
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan
- DOI
- https://doi.org/10.1242/dmm.026476
- Journal volume & issue
-
Vol. 10,
no. 2
pp. 105 – 118
Abstract
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
