title: Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE.
abstract: DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8520, Japan.
authors.forename: Junhui
authors.initials: J
authors.lastname: Yuan
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Tatsui
authors.initials: T
authors.lastname: Nagado
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nozuma
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakamura
authors.forename: Eiji
authors.initials: E
authors.lastname: Matsuura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashiguchi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakiyama
authors.forename: Akiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takashima
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human