What Is CMT-CRYAB?
CMT-CRYAB is a type of CMT caused by autosomal dominant mutations in the CRYAB gene. This gene provides instructions for making alpha-B-crystallin, a small heat-shock protein that acts as a molecular chaperone, helping other proteins fold correctly and protecting cells, including nerve and muscle cells, from stress. Mutations in the CRYAB gene disrupt this chaperone function, leading to impaired nerve signal transmission.
CMT-CRYAB is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.
Clinical Features
CMT-CRYAB has a late onset, typically after age 40. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.
CMT-CRYAB symptoms may include:
- Distal weakness in the feet and lower legs, developing after age 40
- Reduced sensation in the hands and feet
- Muscle atrophy
- Foot drop
- Reduced or absent reflexes
- Congenital cataracts
- Breathing muscle weakness is common
- Additional symptoms not listed here
Disease Course
CMT-CRYAB is slowly progressive following its late onset. Regular cardiac and respiratory monitoring is recommended for affected individuals with this subtype.
Genetic Context
- HGNC-Approved Gene Symbol
- CRYAB
- Gene Full Name
- crystallin alpha B
- HGNC Gene Alias(es)
- CRYA2, HSPB5
- Chromosome
- 11q23.1
- Zygosity of Responsible Variant
- Heterozygous
- Variant Mechanism
-
Dominant-Negative
Details
Confidence:
Low
Prediction:
The literature predicts a dominant-negative mechanism for CMT-CRYAB: alphaB-crystallin functions only as a large oligomer and exchanges subunits with alphaA-crystallin, so the heterozygous p.Arg120Gly allele reported by Cortese et al. (2023) yields a subunit that enters those complexes and degrades the chaperone capacity of the whole assembly. Complete CRYAB nulls instead cause a recessive infantile myofibrillar myopathy whose heterozygous carriers are well, so a halved dose does not produce this dominant disease.
Rationale:
Mutant alphaB-crystallin does not stay apart from the normal protein: it assembles into an irregular high-molecular-weight complex, and co-expressing other small heat-shock chaperones relieves the aggregation, which points to capacity lost inside a shared oligomer rather than a toxin acting alone. A 2025 structural report instead reads the mutant as a constitutively activated chaperone, and confidence stays low while that reading is open.
Updated: July 18, 2026 | By: K. Raymond
