title: 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.
authors.affiliation: Department of Neurology, Neuromuscular Disease Centre (CERNEST), Strasbourg University Hospital, Strasbourg, France.
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.affiliation: Peripheral Neuropathy Group, VIB Department of Molecular Genetics and Institute Born Bunge, University of Antwerp, Antwerpen, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geuens
authors.affiliation: Neuromuscular Disease Centre, Lyon University Hospital, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Petiot
authors.affiliation: Neuromuscular Disease Centre, Nantes University Hospital, Nantes, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Péréon
authors.affiliation: Peripheral Neuropathy Group, VIB Department of Molecular Genetics and Institute Born Bunge, University of Antwerp, Antwerpen, Belgium.
authors.forename: Elias
authors.initials: E
authors.lastname: Adriaenssens
authors.affiliation: Peripheral Neuropathy Group, VIB Department of Molecular Genetics and Institute Born Bunge, University of Antwerp, Antwerpen, Belgium.
authors.forename: Mansour
authors.initials: M
authors.lastname: Haidar
authors.affiliation: Peripheral Neuropathy Group, VIB Department of Molecular Genetics and Institute Born Bunge, University of Antwerp, Antwerpen, Belgium.
authors.forename: Simona
authors.initials: S
authors.lastname: Capponi
authors.affiliation: Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.affiliation: Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
authors.affiliation: Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Dubourg
authors.affiliation: APHP, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Degos
authors.affiliation: APHP, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.affiliation: Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris, France.
authors.forename: Timothée
authors.initials: T
authors.lastname: Lenglet
authors.affiliation: Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.affiliation: Neuromuscular Disease Centre, Nice University Hospital, Nice, France.
authors.forename: Emilien
authors.initials: E
authors.lastname: Delmont
authors.affiliation: Neuromuscular Disease Centre, Marseille University Hospital, APHM, Marseille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.affiliation: Neuromuscular Disease Centre, Montpellier University Hospital, Montpellier, France.
authors.forename: Raul
authors.initials: R
authors.lastname: Juntas Morales
authors.affiliation: Department of Genetics, Bordeaux University Hospital, Bordeaux, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: Biology and Pathology Department, Lyon University Hospital, Bron, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.affiliation: Peripheral Neuropathy Group, VIB Department of Molecular Genetics and Institute Born Bunge, University of Antwerp, Antwerpen, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.affiliation: Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris, France.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stojkovic
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D050888:Heat-Shock Proteins, Small / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D016472:Motor Neuron Disease / Q000175:diagnosis / Q000235:genetics; D005810:Multigene Family; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; C116424:HSPB3 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases
keywords: distal hereditary motor neuropathy; functional validation of novel mutations; peripheral neuropathies; small heat shock proteins