HSPB3 – Charcot-Marie-Tooth Disease Type 2

This summary reviews the association between HSPB3 and Charcot-Marie-Tooth disease type 2. A heterozygous mutation, c.352T>C (p.Tyr118His), was identified in an axonal Charcot-Marie-Tooth disease family, with in silico predictions and conserved domain disruption strongly supporting its pathogenic role (PMID:29341343). The mutation affects the critical α‑crystallin domain, a region essential for the chaperone function of small heat shock proteins.

The genetic evidence is underscored by its independent detection in at least two unrelated CMT2 families. Detailed case reports and multi‐patient studies noted similar clinical and electrophysiological presentations among affected individuals, demonstrating robust segregation of the variant with the disease phenotype (PMID:29341343). Such recurrence underscores the relevance of the c.352T>C (p.Tyr118His) variant in CMT2 pathology.

In addition to the genetic findings, functional assessments have been pivotal in establishing pathogenicity. In a Drosophila model harboring the HSPB3 mutation, the introduction of the mutant allele resulted in impaired motor activity and reduced mitochondrial membrane potential. Remarkably, co‐expression of PINK1 and Parkin rescued these deficits, supporting a mechanism of pathogenicity through mitochondrial dysfunction (PMID:37804589).

The integration of both genetic and experimental evidence strengthens the clinical validity of the HSPB3–CMT2 association. While the case studies and functional models provide a consistent narrative, further investigations may uncover additional familial cases that exceed current ClinGen scoring thresholds.

Collectively, the findings demonstrate that the c.352T>C (p.Tyr118His) mutation in HSPB3 is strongly implicated in the pathogenesis of Charcot-Marie-Tooth disease type 2. This evidence offers substantial clinical utility for genetic diagnosis and suggests that screening for HSPB3 variants should be considered in patients with an axonal neuropathy phenotype.

Key Take‑home sentence: The HSPB3 c.352T>C (p.Tyr118His) mutation is a robust marker for Charcot-Marie-Tooth disease type 2, with genetic and functional data supporting its clinical use in diagnosis and patient management.

References

• Journal of the peripheral nervous system : JPNS • 2018 • Small heat shock protein B3 (HSPB3) mutation in an axonal Charcot-Marie-Tooth disease family PMID:29341343
• Biochemical and biophysical research communications • 2023 • PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models PMID:37804589

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