TY - JOUR
T1 - A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy
AU - Seco, Celia Zazo
AU - Castells-Nobau, Anna
AU - Joo, Seol Hee
AU - Schraders, Margit
AU - Foo, Jia Nee
AU - Van Der Voet, Monique
AU - Velan, S. Sendhil
AU - Nijhof, Bonnie
AU - Oostrik, Jaap
AU - De Vrieze, Erik
AU - Katana, Radoslaw
AU - Mansoor, Atika
AU - Huynen, Martijn
AU - Szklarczyk, Radek
AU - Oti, Martin
AU - Tranebjarg, Lisbeth
AU - Van Wijk, Erwin
AU - Scheffer-De Gooyert, Jolanda M.
AU - Siddique, Saadat
AU - Baets, Jonathan
AU - De Jonghe, Peter
AU - Kazmi, Syed Ali Raza
AU - Sadananthan, Suresh Anand
AU - Van De Warrenburg, Bart P.
AU - Khor, Chiea Chuen
AU - Göpfert, Martin C.
AU - Qamar, Raheel
AU - Schenck, Annette
AU - Kremer, Hannie
AU - Siddiqi, Saima
N1 - Publisher Copyright:
© 2017. Published by The Company of Biologists Ltd.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosislike 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.
AB - A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosislike 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.
KW - Drosophila
KW - Dystonia
KW - FITM2
KW - Hearing impairment
KW - Lipid droplets
KW - Motor development
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U2 - 10.1242/dmm.026476
DO - 10.1242/dmm.026476
M3 - Article
C2 - 28067622
AN - SCOPUS:85012207606
SN - 1754-8403
VL - 10
SP - 105
EP - 118
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
IS - 2
ER -