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

Andoni Echaniz-Laguna, Thomas Geuens, Philippe Petiot, Yann Péréon, Elias Adriaenssens, Mansour Haidar, Simona Capponi, Thierry Maisonobe, Emmanuel Fournier, Odile Dubourg, Bertrand Degos, François Salachas, Timothée Lenglet, Bruno Eymard, Emilien Delmont, Jean Pouget, Raul Juntas Morales, Cyril Goizet, Philippe Latour, Vincent Timmerman, Tanya Stojkovic
Human Mutation. 2017-02-25; 38(5): 556-568
DOI: 10.1002/humu.23189

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1. Hum Mutat. 2017 May;38(5):556-568. doi: 10.1002/humu.23189. Epub 2017 Feb 25.

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

Echaniz-Laguna A(1), Geuens T(2), Petiot P(3), Péréon Y(4), Adriaenssens E(2),
Haidar M(2), Capponi S(2), Maisonobe T(5), Fournier E(5), Dubourg O(5), Degos
B(6), Salachas F(6), Lenglet T(5), Eymard B(5), Delmont E(7), Pouget J(8), Juntas
Morales R(9), Goizet C(10), Latour P(11), Timmerman V(2), Stojkovic T(5).

Author information:
(1)Department of Neurology, Neuromuscular Disease Centre (CERNEST), Strasbourg
University Hospital, Strasbourg, France.
(2)Peripheral Neuropathy Group, VIB Department of Molecular Genetics and
Institute Born Bunge, University of Antwerp, Antwerpen, Belgium.
(3)Neuromuscular Disease Centre, Lyon University Hospital, Lyon, France.
(4)Neuromuscular Disease Centre, Nantes University Hospital, Nantes, France.
(5)Neuromuscular Disease Centre, Hôpital de la Pitié-Salpétrière, APHP, Paris,
(6)APHP, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France.
(7)Neuromuscular Disease Centre, Nice University Hospital, Nice, France.
(8)Neuromuscular Disease Centre, Marseille University Hospital, APHM, Marseille,
(9)Neuromuscular Disease Centre, Montpellier University Hospital, Montpellier,
(10)Department of Genetics, Bordeaux University Hospital, Bordeaux, France.
(11)Biology and Pathology Department, Lyon University Hospital, Bron, France.

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.

© 2017 Wiley Periodicals, Inc.

DOI: 10.1002/humu.23189
PMID: 28144995 [Indexed for MEDLINE]

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