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

Topic: Brain proteins, microglia and lab models

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.

@article{winkelmann2012-22328086,
  author  = {Winkelmann, J. and Lin, L. and Schormair, B. and Kornum, B. R. and Faraco, J. and Plazzi, G. and Melberg, A. and Cornelio, F. and others},
  title   = {{Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy}},
  journal = {Human molecular genetics},
  year    = {2012},
  doi     = {10.1093/hmg/dds035},
  pmid    = {22328086},
  url     = {https://doi.org/10.1093/hmg/dds035}
}

Key findings

• 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.

Why it matters

This study identified mutations in DNMT1 in families with autosomal dominant cerebellar ataxia, deafness and narcolepsy, a condition that includes dementia. It reports no treatment, cure or prevention for Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1093/hmg/dds035
• PubMed: 22328086
• Original source →
• Free full text: Human Molecular Genetics →

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