DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss.

摘要: Background: Mutations in DNA methyltransferase 1 (DNMT1) have been identified 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); 2) cerebellar ataxia, deafness, narcolepsy. Both syndromes mutations targeting sequence (TS) domain (exons 20–21), which is important mediating substrate binding to the DNMT1 catalytic domain. Frontal lobe hypometabolism has documented an HSAN1E family, but memory primary cognitive complaint. The chromosomal location of gene at 19p13.2 linked familial late-onset Alzheimer disease. Methods: We sequenced 41 exons their flanking regions kindreds HSAN1E; 48 patients HSAN1 alone without loss; 3) 5 probands frontotemporal (FTD) kindreds. also exon 20 21 364 autopsy-confirmed disease cases. Results: were specific (no narcolepsy). One family carried previously mutation Tyr495Cys; other a novel Tyr495His, both TS symptoms these include prominent personality, psychiatric manifestations, seizures one onset time later than reported Conclusion: Clinicians should consider presenting FTD or decline who loss. Amino acid Tyr495 hot spot for HSAN1E, distinct from associated