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

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...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics Vol. 21; no. 10; p. 2205
Main Authors: Winkelmann, Juliane, Lin, Ling, Schormair, Barbara, Kornum, Birgitte R, Faraco, Juliette, Plazzi, Giuseppe, Melberg, Atle, Cornelio, Ferdinando, Urban, Alexander E, Pizza, Fabio, Poli, Francesca, Grubert, Fabian, Wieland, Thomas, Graf, Elisabeth, Hallmayer, Joachim, Strom, Tim M, Mignot, Emmanuel
Format: Journal Article
Language:English
Published: England 15.05.2012
Subjects:
Amino Acid Sequence
Cerebellar Ataxia - genetics
Deafness - genetics
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - genetics
Exome
Exons
Genes, Dominant
Humans
Molecular Sequence Data
Mutation
Narcolepsy - genetics
Pedigree
Phenotype
ISSN:1460-2083, 1460-2083
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1460-2083
1460-2083
DOI:10.1093/hmg/dds035