dHMN-2B

Genetic Context

HGNC-Approved Gene Symbol

HSPB1

Gene Full Name

heat shock protein family B (small) member 1

HGNC Gene Alias(es)

HSP27

Chromosome

7q11.23

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
Medium

Prediction:
Functional evidence supports a toxic gain-of-function mechanism for dHMN-2B: heterozygous HSPB1 mutants acquire interactions the wild-type small heat-shock protein does not make, binding tubulin and HDAC6, lowering tubulin acetylation, destabilizing neurofilament assembly, and stalling cargo movement along the long motor axons that fail first in dHMN. HDAC6 inhibition restores axonal transport and motor performance in mutant mice, pointing to an acquired activity rather than reduced chaperone dosage. Whether mutant subunits also drag wild-type protein down inside the oligomer is unsettled, and the grade is medium on that point.

Rationale:
Tubulin and HDAC6 binding by mutant HSP27 is an activity the normal protein never performs, and the resulting tubulin hypo-acetylation accounts for the transport failure in distal motor axons where these families show weakness with minimal sensory signs. Pharmacological rescue by HDAC6 inhibition is the strongest argument for an acquired toxic function; the competing dominant-negative pull on the chaperone oligomer keeps the mechanism partly open.

ClinVar Pathogenic Variants

View HSPB1 ClinVar Variants

ClinGen Curation

View HSPB1 ClinGen Curation

dHMN-2B OMIM Entry

dHMN-2B OMIM

HSPB1 OMIM Entry

HSPB1 OMIM