CMT-DRP2

DRP2 | 2015

What Is CMT-DRP2?

CMT-DRP2 is a type of CMT caused by mutations in the DRP2 gene. This gene provides instructions for making dystrophin related protein 2, a component of the periaxin-DRP2-dystroglycan complex that anchors and stabilizes the outer myelin layer of Schwann cells, forming structures called Cajal bands. Mutations in the DRP2 gene disrupt this complex, leading to impaired nerve signal transmission.

CMT-DRP2 is X-linked dominant. This means the gene lives on the X chromosome, and in people with two X chromosomes (chromosomal females), a mutation in one copy of the gene causes CMT. For individuals with one X and one Y chromosome (chromosomal males), a mutation in their single copy of the gene is sufficient to cause CMT.

When a female has CMT-DRP2, each of her children has a 50% chance of inheriting her CMT. In contrast, a chromosomal male with CMT-DRP2 will pass it to all his daughters but none of his sons because males pass their X chromosome only to their daughters.

Clinical Features

The age of symptom onset in CMT-DRP2 is variable, ranging from childhood to adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities, consistent with an intermediate form of CMT.

CMT-DRP2 symptoms may include:

  • Weakness in the feet and lower legs
  • Muscle atrophy
  • Foot drop
  • Reduced or absent reflexes
  • Reduced sensation
  • A steppage-style walking pattern
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Progressive involvement of the hands and forearms
  • Difficulty with fine motor skills and manual dexterity
  • Additional symptoms not listed here

Disease Course

CMT-DRP2 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
CMT-DRP2

Classification
Unclassified Subtypes

Neuropathy Type
Intermediate

Inheritance Pattern
X-linked dominant

Genetic Context

HGNC-Approved Gene Symbol
DRP2

Gene Full Name
Dystrophin Related Protein 2

Chromosome
Xq22.1

Zygosity of Responsible Variant
Hemizygous (Male) / Heterozygous (Female)

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Haploinsufficiency

Confidence:
Medium

Prediction:
The literature predicts a loss-of-function mechanism for CMT-DRP2: the reported X-linked hemizygous nonsense variant abolishes DRP2, disrupting the periaxin-DRP2-dystroglycan complex and Cajal bands in Schwann cells. Because restored wild-type DRP2 is predicted to rescue the complex and a single absent copy suffices in this dosage-sensitive X-linked setting, the evidence supports loss of function rather than a dominant-negative or gain-of-function effect, on limited data.

Rationale:
The X-linked nonsense allele abolishes DRP2 and disrupts the periaxin-DRP2-dystroglycan complex through simple loss that restored wild-type is predicted to rescue. The haploinsufficiency label is a slight stretch for a hemizygous null and rests on limited data, holding confidence at medium.

ClinVar Pathogenic Variants

View CMT-DRP2 ClinVar Variants

DRP2 OMIM Entry

DRP2 OMIM

More Info

CMT-DRP2 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Absence of Dystrophin Related Protein-2 Disrupts Cajal Bands in a Patient with Charcot-Marie-Tooth Disease

Authors

Brennan, K. M., Bai, Y., Pisciotta, C., Wang, S., Feely, S. M., Hoegger, M., Gutmann, L., Moore, S. A., Gonzalez, M., Sherman, D. L., Brophy, P. J., Züchner, S., & Shy, M. E.

Publication Date
July 7, 2015

DOI
10.1016/j.nmd.2015.07.001

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

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