title: A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.
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.
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Celia
authors.initials: C
authors.lastname: Zazo Seco
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Castells-Nobau
authors.affiliation: Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Joo
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.affiliation: Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore.
authors.forename: Jia Nee
authors.initials: JN
authors.lastname: Foo
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van der Voet
authors.affiliation: Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore.|Singapore Institute for Clinical Sciences, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 117609, Singapore.
authors.forename: S Sendhil
authors.initials: SS
authors.lastname: Velan
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Nijhof
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Vrieze
authors.affiliation: Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Katana
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan.
authors.forename: Atika
authors.initials: A
authors.lastname: Mansoor
authors.affiliation: Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Huynen
authors.affiliation: Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Radek
authors.initials: R
authors.lastname: Szklarczyk
authors.affiliation: The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Department of Molecular Developmental Biology, Radboud University, Nijmegen 6525GA, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Oti
authors.affiliation: 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, Head and Neck Surgery and Audiology, Bispebjerg Hospital/Rigshospitalet, Copenhagen 2400, Denmark.|Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup 2600, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjærg
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: Scheffer-de Gooyert
authors.affiliation: National Institute of Rehabilitation Medicine (NIRM), Islamabad 44000, Pakistan.
authors.forename: Saadat
authors.initials: S
authors.lastname: Siddique
authors.affiliation: Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerp 2000, Belgium.|Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp 2000, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp 2610, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerp 2000, Belgium.|Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp 2000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: de Jonghe
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan.
authors.forename: Syed Ali Raza
authors.identifier: 0000-0002-0144-5496
authors.initials: SA
authors.lastname: Kazmi
authors.affiliation: Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 138667, Singapore.|Singapore Institute for Clinical Sciences, A*STAR, Clinical Imaging Research Centre, NUS-A*STAR, Singapore 117609, Singapore.
authors.forename: Suresh Anand
authors.initials: SA
authors.lastname: Sadananthan
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Department of Neurology, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.affiliation: Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore.|Singapore Eye Research Institute, Singapore 168751, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 168751, Singapore.
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: Department of Cellular Neurobiology, University of Göttingen, Göttingen 37077, Germany.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Göpfert
authors.affiliation: COMSATS Institute of Information Technology, Islamabad 45550, Pakistan.|Al-Nafees Medical College & Hospital, Isra University, Islamabad 45600, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.affiliation: 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.|Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Hannie
authors.identifier: 0000-0002-0841-8693
authors.initials: H
authors.lastname: Kremer
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan.
authors.forename: Saima
authors.identifier: 0000-0002-9027-9839
authors.initials: S
authors.lastname: Siddiqi
mesh_terms: D050154:Adiposity; D000818:Animals; D001301:Audiometry, Pure-Tone; D001483:Base Sequence; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D054062:Deaf-Blind Disorders / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D004421:Dystonia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D034381:Hearing Loss / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007057:Ichthyosis / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008607:Intellectual Disability / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D066292:Lipid Droplets / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008124:Locomotion; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity; D009154:Mutation / Q000235:genetics*; D009896:Optic Atrophy / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D011984:Sensory Receptor Cells / Q000473:pathology*; D000073359:Exome Sequencing; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D029721:Drosophila Proteins; C575964:FITM2 protein, human; D008565:Membrane Proteins
keywords: Drosophila; Dystonia; FITM2; Hearing impairment; Lipid droplets; Motor development