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Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE
Author(s) -
Yuan Junhui,
Higuchi Yujiro,
Nagado Tatsui,
Nozuma Satoshi,
Nakamura Tomonori,
Matsuura Eiji,
Hashiguchi Akihiro,
Sakiyama Yusuke,
Yoshimura Akiko,
Takashima Hiroshi
Publication year - 2013
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1111/jns5.12012
Subject(s) - missense mutation , exon , cerebellar ataxia , genetics , mutation , ataxia , biology , neuroscience , gene
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.