DNMT1

At least four DNMT1 gene mutations have been identified in people with a nervous system disorder called autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN). Features of this disorder include difficulty coordinating movements (ataxia), hearing loss caused by abnormalities of the inner ear (sensorineural deafness), and excessive daytime sleepiness (narcolepsy). Cognitive decline occurs as the disorder progresses. Numbness, tingling, or pain in the arms and legs (sensory neuropathy) can also occur. Affected individuals usually survive into their forties or fifties.

The DNMT1 gene mutations associated with this disorder affect a region of the DNA methyltransferase 1 enzyme, known as the targeting sequence, that helps direct the methylation process to the correct segments of DNA. As a result of these mutations, methylation is abnormal, which affects the expression of multiple genes. Maintenance of the neurons that make up the nervous system is disrupted, leading to the signs and symptoms of ADCADN.

At least 10 DNMT1 gene mutations have been identified in people with another nervous system disorder called hereditary sensory and autonomic neuropathy type IE (HSAN IE). As in ADCADN, (described above), people with HSAN IE have sensorineural deafness, sensory neuropathy, cognitive decline, and a shortened lifespan. However, they typically do not have the ataxia or narcolepsy that occurs in ADCADN, and the sensory neuropathy begins earlier in life in people with HSAN IE. Seizures can also occur in this disorder.

DNMT1 gene mutations that cause HSAN IE, like those that cause ADCADN, affect the targeting sequence of the DNA methyltransferase 1 enzyme. However, most of the mutations that cause HSAN IE occur in a part of the gene called exon 20 and affect one end of the enzyme's targeting sequence, while the mutations that cause ADCADN are mostly in a nearby part of the gene called exon 21 and affect the other end of the enzyme's targeting sequence.

As a result of the DNMT1 gene mutations, methylation is abnormal and maintenance of the neurons that make up the nervous system is impaired. However, it is not known how the mutations cause the specific signs and symptoms of HSAN IE, or how mutations affecting the targeting sequence of the DNA methyltransferase 1 enzyme can cause either HSAN IE or ADCADN.

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Several normal variations (polymorphisms) in the DNMT1 gene have been associated with an increased risk of cancer, including cancers of the breast and stomach. These variations, which are found in cells throughout the body and can be passed on from parent to child, may affect the activity of the DNA methyltransferase 1 enzyme and its role in gene silencing. Changes in the silencing of particular genes can lead to abnormal cell growth and division and increase the risk of cancer.

In addition, increased activity (overexpression) of the DNMT1 gene has been identified in certain brain cancers called gliomas. The genetic changes involved in this overexpression are somatic, which means that they occur only in the tumor cells and are not inherited. Researchers suggest that overexpression of the DNMT1 gene may result in methylation and silencing of genes called tumor suppressors. When tumor suppressor genes are silenced, cells can grow and divide unchecked, which can lead to cancer.