Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations

Abstract

In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.

Small heat shock proteins in neurodegenerative diseases

“…Patients with HSPB1 mutations usually present with progressive weakness of the legs, with bilateral foot drop often arising as the first symptom. The age of onset is usually in the second decade of life, although onsets up to the seventh decade of life have also been reported (Harding and Thomas 1980;Capponi et al 2011;Echaniz-Laguna et al 2017a;Rossor et al 2017). Disease progression is slow and a significant percentage of patients develop upper limb weakness over the years, leading to loss of ambulation, resulting eventually in wheelchair dependence.…”

“…Patients may also suffer from mild sensory involvement, although the degree of involvement is highly variable and can even differ between affected members of the same family (Rossor et al 2017). Other common features include mildly elevated creatine kinase levels, foot deformities, and thigh and hand weakness; and CNS involvement was observed in 5-10% of the patients (Echaniz-Laguna et al 2017a, Rossor et al 2017). So far, over 30 different mutations have been found in the HSPB1 gene leading to inherited peripheral neuropathies ( Fig.…”

Dysregulated interactions triggered by a neuropathy-causing mutation in the IPV motif of HSP27

“…Similar to P182L, the S187L variant of HSP27 was found to aggregate in vivo (13), but it remains unclear if the aggregation is caused by increasing the hydrophobicity of the disordered CTR or if the mutation affects the binding affinity of the IxI/V motif. It has been proposed that the flexible CTR provides solubility to sHSP oligomers (71), so altering the hydrophobicity of this region may contribute to insolubility.…”

“…Dysregulation of the activity or expression of HSP27 can result in debilitating diseases, including cancers (9,10), neurodegenerative diseases (11), and neuropathies (12). Over 30 heritable HSP27 mutations are implicated in Charcot-Marie-Tooth (CMT) disease (13)(14)(15), a group of neuropathies that affects ca. 1 in 2500 individuals and is the most common inherited disorder involving the peripheral nervous system (16,17).…”

Possible Function of Molecular Chaperones in Diseases Caused by Propagating Amyloid Aggregates

“…Small Hsps have been shown to efficiently counteract the aggregation of many pathogenic proteins, including α-synuclein, huntingtin, and ataxins. The importance of these chaperones was demonstrated in studies showing that the hereditary mutations in HSPB1/Hsp27 and the associated reduced ability to maintain proteostasis gave rise to a great number of neurodegenerative disorders, including Charcot-Marie-Tooth disease and ALS (Echaniz-Laguna et al, 2017). …”