In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) identified a heterozygous c.404C-T transition in exon 2 of the HSPB1 gene, resulting in a ser135-to-phe (S135F) substitution. In affected members of an unrelated family from the United Kingdom with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), the authors identified the same mutation in heterozygosity. The S135F mutation occurs in a highly conserved alpha-crystallin domain of the protein. In vitro expression of the mutant protein resulted in reduced viability of neuronal cells and impaired neurofilament assembly. Evgrafov et al. (2004) suggested that these deficits may be responsible for premature axonal degeneration, which underlies both CMT and dHMN.
Houlden et al. (2008) identified a heterozygous S135F mutation in affected members of a large family with HMND3. The mean age at onset was 21 years, and sensory abnormalities were not present.
Variant Function
In cultured mouse motor neurons, Zhai et al. (2007) showed that expression of S135F-mutant HSPB1 led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL (162280) protein. The 2 proteins were found to associate together, and the S135F mutant had a dominant effect. Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to disruption of the neurofilament network and aggregation of NEFL, and wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E (607684) and CMT2F.
