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

doi:10.1242/dmm.026476

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 BaetsPeter 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

Department of Clinical Medicine

8 Citations (Scopus)

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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.

Original language	English
Journal	Disease models & mechanisms
Volume	10
Pages (from-to)	105-118
Number of pages	14
ISSN	1754-8403
DOIs	https://doi.org/10.1242/dmm.026476
Publication status	Published - 1 Feb 2017

Keywords

Adiposity
Animals
Audiometry, Pure-Tone
Base Sequence
Child
Codon, Nonsense/genetics
Deaf-Blind Disorders/blood
Disease Models, Animal
Drosophila Proteins/genetics
Drosophila melanogaster/genetics
Dystonia/blood
Female
Gene Expression Regulation
Gene Knockdown Techniques
HEK293 Cells
Hearing Loss/genetics
Homozygote
Humans
Ichthyosis/complications
Intellectual Disability/blood
Lipid Droplets/metabolism
Liver/metabolism
Locomotion
Male
Membrane Proteins/genetics
Motor Activity
Mutation/genetics
Optic Atrophy/blood
Pedigree
Sensory Receptor Cells/pathology
Whole Exome Sequencing
Young Adult

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10.1242/dmm.026476Licence: CC BY

A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathyFinal published version, 3.52 MBLicence: CC BY

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Zazo Seco, C., Castells-Nobau, A., Joo, S.-H., Schraders, M., Foo, J. N., van der Voet, M., Velan, S. S., Nijhof, B., Oostrik, J., de Vrieze, E., Katana, R., Mansoor, A., Huynen, M., Szklarczyk, R., Oti, M., Tranebjærg, L., van Wijk, E., Scheffer-de Gooyert, J. M., Siddique, S., ... Siddiqi, S. (2017). A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy. Disease models & mechanisms, 10, 105-118. https://doi.org/10.1242/dmm.026476

Zazo Seco, C, Castells-Nobau, A, Joo, S-H, Schraders, M, Foo, JN, van der Voet, M, Velan, SS, Nijhof, B, Oostrik, J, de Vrieze, E, Katana, R, Mansoor, A, Huynen, M, Szklarczyk, R, Oti, M, Tranebjærg, L, van Wijk, E, Scheffer-de Gooyert, JM, Siddique, S, Baets, J, de Jonghe, P, Kazmi, SAR, Sadananthan, SA, van de Warrenburg, BP, Khor, CC, Göpfert, MC, Qamar, R, Schenck, A, Kremer, H & Siddiqi, S 2017, 'A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy', Disease models & mechanisms, vol. 10, pp. 105-118. https://doi.org/10.1242/dmm.026476

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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.",

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author = "{Zazo Seco}, Celia and Anna Castells-Nobau and Seol-Hee Joo and Margit Schraders and Foo, {Jia Nee} and {van der Voet}, Monique and Velan, {S Sendhil} and Bonnie Nijhof and Jaap Oostrik and {de Vrieze}, Erik and Radoslaw Katana and Atika Mansoor and Martijn Huynen and Radek Szklarczyk and Martin Oti and Lisbeth Tranebj{\ae}rg and {van Wijk}, Erwin and {Scheffer-de Gooyert}, {Jolanda M} and Saadat Siddique and Jonathan Baets and {de Jonghe}, Peter and Kazmi, {Syed Ali Raza} and Sadananthan, {Suresh Anand} and {van de Warrenburg}, {Bart P} and Khor, {Chiea Chuen} and G{\"o}pfert, {Martin C} and Raheel Qamar and Annette Schenck and Hannie Kremer and Saima Siddiqi",

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doi = "10.1242/dmm.026476",

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T1 - A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

AU - Zazo Seco, Celia

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 - Tranebjærg, 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

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, 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.

AB - 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.

KW - Adiposity

KW - Animals

KW - Audiometry, Pure-Tone

KW - Base Sequence

KW - Child

KW - Codon, Nonsense/genetics

KW - Deaf-Blind Disorders/blood

KW - Disease Models, Animal

KW - Drosophila Proteins/genetics

KW - Drosophila melanogaster/genetics

KW - Dystonia/blood

KW - Female

KW - Gene Expression Regulation

KW - Gene Knockdown Techniques

KW - HEK293 Cells

KW - Hearing Loss/genetics

KW - Homozygote

KW - Humans

KW - Ichthyosis/complications

KW - Intellectual Disability/blood

KW - Lipid Droplets/metabolism

KW - Liver/metabolism

KW - Locomotion

KW - Male

KW - Membrane Proteins/genetics

KW - Motor Activity

KW - Mutation/genetics

KW - Optic Atrophy/blood

KW - Pedigree

KW - Sensory Receptor Cells/pathology

KW - Whole Exome Sequencing

KW - Young Adult

U2 - 10.1242/dmm.026476

DO - 10.1242/dmm.026476

M3 - Journal article

C2 - 28067622

SN - 1754-8403

VL - 10

SP - 105

EP - 118

JO - Disease models & mechanisms

JF - Disease models & mechanisms

ER -

A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

Abstract

Keywords

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