HSN-1E

DNMT1 | 2011

What Is HSN-1E?

HSN-1E is a type of CMT caused by autosomal dominant mutations in the DNMT1 gene. This gene provides instructions for making an enzyme that maintains the pattern of DNA methylation essential to normal nerve cell function. Mutations in the DNMT1 gene disrupt this function, leading to impaired nerve signal transmission.

HSN-1E is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.

Clinical Features

The age of symptom onset in HSN-1E is variable, ranging from childhood to adulthood. The disease involves loss of sensation that begins in the hands and feet (glove-and-stocking distribution) and progresses over time towards the center of the body. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.

HSN-1E symptoms may include:

  • Progressive loss of sensation in the feet and hands
  • Loss of pain and temperature sensation
  • Reduced or absent reflexes
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Distal weakness that develops as the disease progresses
  • Foot drop
  • Additional symptoms not listed here

Disease Course

HSN-1E shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
HSN-1E

Classification
HSN

Neuropathy Type
Axonal

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
DNMT1

Gene Full Name
DNA Methyltransferase 1

HGNC Gene Alias(es)
DNMT

Chromosome
19p13.2

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Complex

Details

Mechanistic basis:
Mixed

Confidence:
Medium

Prediction:
The literature predicts a complex mechanism for HSN-1E: the dominant DNMT1 RFTS-domain alleles both cause misfolding, premature degradation, and reduced maintenance methyltransferase activity, a partial loss producing a globally hypomethylated methylome, and generate mislocalized, aggregating mutant protein contributing a toxic gain. Because a single dominant allele class carries both, the evidence supports a mixed mechanism rather than pure haploinsufficiency, consistent with heterozygous nulls not reproducing the disease.

Rationale:
The same dominant DNMT1 RFTS-domain alleles both partially lose maintenance-methylation activity, producing global hypomethylation, and add an independent toxic gain through mislocalization and aggregation, so a complex mixed mechanism fits, consistent with heterozygous nulls not reproducing the disease. The toxic-gain arm is less firmly established, holding confidence at medium.

ClinVar Pathogenic Variants

View HSN-1E ClinVar Variants

HSN-1E OMIM Entry

HSN-1E OMIM

DNMT1 OMIM Entry

DNMT1 OMIM

More Info

HSN-1E Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Mutations in DNMT1 Cause Hereditary Sensory Neuropathy with Dementia and Hearing Loss

Authors

Klein, C. J., Botuyan, M. V., Wu, Y., Ward, C. J., Nicholson, G. A., Hammans, S., Hojo, K., Yamanishi, H., Karpf, A. R., Wallace, D. C., Simon, M., Lander, C., Boardman, L. A., Cunningham, J. M., Smith, G. E., Litchy, W. J., Boes, B., Atkinson, E. J., Middha, S., B Dyck, P. J., … Dyck, P. J.

Publication Date
May 1, 2011

DOI
10.1038/ng.830

Updated: July 18, 2026 | By: K. Raymond

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