Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

Juliane Winkelmann; Ling Lin; Barbara Schormair; Birgitte R Kornum; Juliette Faraco; Giuseppe Plazzi; Atle Melberg; Ferdinando Cornelio; Alexander E Urban; Fabio Pizza; Francesca Poli; Fabian Grubert; Thomas Wieland; Elisabeth Graf; Joachim Hallmayer; Tim M Strom; Emmanuel Mignot

doi:10.1093/hmg/dds035

Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

Juliane Winkelmann, Ling Lin, Barbara Schormair, Birgitte R Kornum, Juliette Faraco, Giuseppe Plazzi, Atle Melberg, Ferdinando Cornelio, Alexander E Urban, Fabio Pizza, Francesca Poli, Fabian Grubert, Thomas Wieland, Elisabeth Graf, Joachim Hallmayer, Tim M Strom, Emmanuel Mignot

Afdeling for Almen Medicin

156 Citationer (Scopus)

Abstract

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	21
Udgave nummer	10
Sider (fra-til)	2205-10
Antal sider	6
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/dds035
Status	Udgivet - 15 maj 2012

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10.1093/hmg/dds035

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Winkelmann, J., Lin, L., Schormair, B., Kornum, B. R., Faraco, J., Plazzi, G., Melberg, A., Cornelio, F., Urban, A. E., Pizza, F., Poli, F., Grubert, F., Wieland, T., Graf, E., Hallmayer, J., Strom, T. M., & Mignot, E. (2012). Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Human Molecular Genetics, 21(10), 2205-10. https://doi.org/10.1093/hmg/dds035

Winkelmann, J, Lin, L, Schormair, B, Kornum, BR, Faraco, J, Plazzi, G, Melberg, A, Cornelio, F, Urban, AE, Pizza, F, Poli, F, Grubert, F, Wieland, T, Graf, E, Hallmayer, J, Strom, TM & Mignot, E 2012, 'Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy', Human Molecular Genetics, bind 21, nr. 10, s. 2205-10. https://doi.org/10.1093/hmg/dds035

@article{1bcfb34b709247e5930c3f9e47ccb874,

title = "Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy",

abstract = "Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.",

keywords = "Amino Acid Sequence, Cerebellar Ataxia/genetics, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases/genetics, Deafness/genetics, Exome, Exons, Genes, Dominant, Humans, Molecular Sequence Data, Mutation, Narcolepsy/genetics, Pedigree, Phenotype",

author = "Juliane Winkelmann and Ling Lin and Barbara Schormair and Kornum, {Birgitte R} and Juliette Faraco and Giuseppe Plazzi and Atle Melberg and Ferdinando Cornelio and Urban, {Alexander E} and Fabio Pizza and Francesca Poli and Fabian Grubert and Thomas Wieland and Elisabeth Graf and Joachim Hallmayer and Strom, {Tim M} and Emmanuel Mignot",

year = "2012",

month = may,

day = "15",

doi = "10.1093/hmg/dds035",

language = "English",

volume = "21",

pages = "2205--10",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "10",

}

TY - JOUR

T1 - Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

AU - Winkelmann, Juliane

AU - Lin, Ling

AU - Schormair, Barbara

AU - Kornum, Birgitte R

AU - Faraco, Juliette

AU - Plazzi, Giuseppe

AU - Melberg, Atle

AU - Cornelio, Ferdinando

AU - Urban, Alexander E

AU - Pizza, Fabio

AU - Poli, Francesca

AU - Grubert, Fabian

AU - Wieland, Thomas

AU - Graf, Elisabeth

AU - Hallmayer, Joachim

AU - Strom, Tim M

AU - Mignot, Emmanuel

PY - 2012/5/15

Y1 - 2012/5/15

N2 - Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

AB - Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

KW - Amino Acid Sequence

KW - Cerebellar Ataxia/genetics

KW - DNA (Cytosine-5-)-Methyltransferase 1

KW - DNA (Cytosine-5-)-Methyltransferases/genetics

KW - Deafness/genetics

KW - Exome

KW - Exons

KW - Genes, Dominant

KW - Humans

KW - Molecular Sequence Data

KW - Mutation

KW - Narcolepsy/genetics

KW - Pedigree

KW - Phenotype

U2 - 10.1093/hmg/dds035

DO - 10.1093/hmg/dds035

M3 - Journal article

C2 - 22328086

SN - 0964-6906

VL - 21

SP - 2205

EP - 2210

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 10

ER -

Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

Abstract

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