Submission Details

HSPB1 was first reported in relation to Autosomal Dominant CMT2 and dHMN in 2004 (Evgrafov et al., PMID: 15122254). The disease is characterized by a predominantly motor neuropathy, with distal atrophy and weakness, and only late, subclinical sensory signs. The inheritance pattern of the two diseases is reported to be autosomal dominant. It has been proposed that mutations located in the C-terminal tail of the protein cause dHMN, however, is not supported by genotype-phenotype associations and the same variants can be associated with either phenotype in different families and within the same family. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, dHMN type 2B (OMIM:608634). Recessive inheritance has been also described and will be reviewed separately. Sixteen variants (13 missense, 3 nonsense) that have been reported in 33 probands in 10 publications (PMIDs: 15122254, 18832141, 18952241, 18344398, 16155736, 16087758, 20870250, 19435728, 22734906, 29381233) More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached genetic evidence. A gain of function mechanism of pathogenicity is hypnotized for most of HSPB1 disease-associated variants on the basis of the tendency of mutant proteins to aggregate, sequestering the WT protein, the aberrant dimerization and interaction with substrate proteins, like Neurofilaments, by mutant HSPB1 proteins and the absence of a peripheral nervous system phenotype in KO mice. This gene-disease association is also supported by several transgenic models. In one of them (PMIDs: 21785432), HSPB1 S135F mutation (the most common CMT-associated HSPB1 variant) expressed selectively in neurons induce progressive motor impairment, signs of sensory defects and electrophysiological signs of axonal neuropathy. DRG neurons expressing this variant show impaired mitochondrial transport and reduced acetylated tubulin. The treatment with HDAC6, a tubulin de-acetylator, rescues the motor phenotype. Also transgenic mice expressing HSPB1 P182L mutation in neurons showed motor impairment, axonal loss and denervation. In summary, HSPB1 is definitively associated with autosomal dominant CMT2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.