Echaniz-Laguna A, Geuens T, Petiot P, Péréon Y, Adriaenssens E, Haidar M, Capponi S, Maisonobe T, Fournier E, Dubourg O, Degos B, Salachas F, Lenglet T, Eymard B, Delmont E, Pouget J, Morales R, Goizet C, Latour P, Timmerman V, Stojkovic T.
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 (4 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 4 HSPB8 mutations, including respectively 5 and 3 not previously reported. Transmission was either dominant (78%), recessive (3%) or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, Gln128Arg) cause hyperphosphorylation of neurofilaments, while the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs, 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.