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

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 -