HSPB1 – Charcot-Marie-Tooth disease axonal type 2F

Charcot-Marie-Tooth disease axonal type 2F (CMT2F) is an autosomal dominant peripheral neuropathy caused by mutations in the small heat-shock protein gene HSPB1 (HSP27), which encodes a chaperone critical for cytoskeletal maintenance. Initial linkage in a Russian family localized CMT2F to 7q11-q21 and identified a segregating HSPB1 missense mutation by candidate sequencing ([PMID:15122254]). Subsequent screening of 301 CMT and 115 distal HMN patients confirmed the original variant and uncovered four additional HSPB1 missense alleles in independent families, demonstrating recurrent dominant-negative and gain-of-function effects in the α-crystallin domain ([PMID:15122254]).

Additional case reports have expanded the mutational and phenotypic spectrum: a Sardinian pedigree (13 affected relatives) harboring R127W (c.379C>T (p.Arg127Trp)) revealed intrafamilial variability spanning CMT2F and dHMN features ([PMID:20660910]); an Italian patient with T180I (c.539C>T (p.Thr180Ile)) presented pure motor axonal neuropathy ([PMID:20870250]); and a Japanese cohort (13/1030 IPN patients) identified both known and novel HSPB1 variants, including truncating alleles, with 1.3% mutation prevalence ([PMID:29381233]). Together, these studies report >30 distinct HSPB1 variants in >80 individuals.

The inheritance is autosomal dominant, supported by co-segregation in multiple multigenerational pedigrees with 13 affected relatives in one family ([PMID:20660910]). Functional assays in neuronal cells transfected with mutant HSPB1 demonstrate reduced cell viability and disrupted neurofilament assembly, implicating a dominant-negative mechanism ([PMID:15122254]). Transgenic mice overexpressing mutant HSPB1 (R136W) develop age-dependent motor axonopathy with neurofilament cytoskeletal defects, recapitulating human pathology ([PMID:22521462]).

Mechanistically, many HSPB1 mutations enhance monomerization and aberrant client protein interactions, leading to microtubule stabilization and impaired axonal transport in peripheral neurons ([PMID:22031878]; [PMID:20178975]). This converges on a gain-of-toxic-function model, although haploinsufficiency may contribute for some truncating alleles.

In summary, the association between HSPB1 and CMT2F is supported by robust segregation, a broad variant spectrum with recurrent hotspots in the α-crystallin domain, and concordant in vitro and in vivo functional data. HSPB1 genetic testing has clear diagnostic utility in CMT2F and related dHMN phenotypes.

Key take-home: Autosomal dominant HSPB1 mutations cause CMT2F through dominant-negative and gain-of-function effects on cytoskeletal chaperoning, warranting inclusion in neuropathy gene panels.

References

• Nature genetics • 2004 • Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [PMID:15122254]
• Journal of neurology, neurosurgery, and psychiatry • 2010 • Heat shock protein 27 R127W mutation: evidence of a continuum between axonal Charcot-Marie-Tooth and distal hereditary motor neuropathy. [PMID:20660910]
• Journal of the peripheral nervous system : JPNS • 2018 • Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan. [PMID:29381233]
• Neurobiology of disease • 2012 • Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice. [PMID:22521462]

Evidence Based Scoring (AI generated)