HSPB1 – Distal Hereditary Motor Neuropathy

Autosomal dominant mutations in HSPB1, encoding small heat shock protein 27 (HSP27), cause distal hereditary motor neuropathy (dHMN; MONDO:0018894) characterized by progressive distal muscle weakness without significant sensory loss. The gene–disease link is supported by multiple unrelated probands, large pedigrees with segregation, and concordant functional studies.

Genetic evidence includes at least 28 unrelated index patients with HSPB1 variants in cohorts of distal motor neuropathy ([PMID:28144995]) and segregation of the R127W HSPB1 mutation in a Sardinian family with 13 affected relatives ([PMID:20660910]). The variant spectrum is dominated by heterozygous missense changes in the α-crystallin domain and C-terminus, including recurrent p.Arg136Leu and truncating p.Gln175Ter alleles. Founder or recurrent variants (e.g., p.Arg136Leu) occur in multiple dHMN and CMT2 cohorts with frequencies up to 8% ([PMID:22176143]).

Case reports and series document onset from adolescence to late adulthood, intrafamilial variability, and rare de novo events. Segregation and case counts exceed ClinGen thresholds for a Strong assignment. A representative coding change is c.523C>T (p.Gln175Ter).([PMID:22734906])

Functional assays reveal that neuropathy‐associated HSPB1 mutants exhibit increased monomerization and hyperactive chaperone activity ([PMID:20178975]), aberrant binding to neurofilament and tubulin leading to aggregation and microtubule stabilization in neuronal cells ([PMID:16368711], [PMID:22031878]). These data support a toxic gain‐of‐function mechanism disrupting axonal transport and cytoskeletal dynamics.

No compelling contradictory evidence has been reported. The combined genetic and experimental findings establish a robust association between heterozygous HSPB1 variants and dHMN.

Key Take-home: HSPB1 mutation screening is essential for the molecular diagnosis of autosomal dominant distal hereditary motor neuropathy and can guide genetic counseling and variant interpretation.

References

• Human mutation • 2017 • Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations PMID:28144995
• 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 • 2012 • A novel p.Gln175X [corrected] premature stop mutation in the C-terminal end of HSP27 is a cause of CMT2. PMID:22734906
• Journal of the peripheral nervous system : JPNS • 2011 • HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients. PMID:22176143
• The Journal of biological chemistry • 2010 • Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy. PMID:20178975
• The Journal of neuroscience • 2011 • Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. PMID:22031878

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