A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy
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 nonse...
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| Language: | English |
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The Company of Biologists
2017-02-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/10/2/105 |
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Article |
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DOAJ |
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English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy Disease Models & Mechanisms FITM2 Lipid droplets Drosophila Hearing impairment Motor development Dystonia |
| author_facet |
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 |
| author_sort |
Celia Zazo Seco |
| title |
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy |
| title_short |
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy |
| title_full |
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy |
| title_fullStr |
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy |
| title_full_unstemmed |
A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy |
| title_sort |
homozygous fitm2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy |
| publisher |
The Company of Biologists |
| series |
Disease Models & Mechanisms |
| issn |
1754-8403 1754-8411 |
| publishDate |
2017-02-01 |
| description |
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. |
| topic |
FITM2 Lipid droplets Drosophila Hearing impairment Motor development Dystonia |
| url |
http://dmm.biologists.org/content/10/2/105 |
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doaj-61e74f9ef396439ebd381addcbedf9712020-11-25T02:31:30ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112017-02-0110210511810.1242/dmm.026476026476A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathyCelia Zazo Seco0Anna Castells-Nobau1Seol-hee Joo2Margit Schraders3Jia Nee Foo4Monique van der Voet5S. Sendhil Velan6Bonnie Nijhof7Jaap Oostrik8Erik de Vrieze9Radoslaw Katana10Atika Mansoor11Martijn Huynen12Radek Szklarczyk13Martin Oti14Lisbeth Tranebjærg15Erwin van Wijk16Jolanda M. Scheffer-de Gooyert17Saadat Siddique18Jonathan Baets19Peter de Jonghe20Syed Ali Raza Kazmi21Suresh Anand Sadananthan22Bart P. van de Warrenburg23Chiea Chuen Khor24Martin C. Göpfert25Raheel Qamar26Annette Schenck27Hannie Kremer28Saima Siddiqi29 Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine (ICMM), The Panum Institute, University of Copenhagen, Copenhagen 2200, Denmark Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands National Institute of Rehabilitation Medicine (NIRM), Islamabad 44000, Pakistan Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany COMSATS Institute of Information Technology, Islamabad 45550, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan 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.http://dmm.biologists.org/content/10/2/105FITM2Lipid dropletsDrosophilaHearing impairmentMotor developmentDystonia |