title: Chaperonopathies: Spotlight on Hereditary Motor Neuropathies.
abstract: Distal hereditary motor neuropathies (dHMN) are a group of rare hereditary neuromuscular disorders characterized by an atrophy that affects peroneal muscles in the absence of sensory symptoms. To date, 23 genes are thought to be responsible for dHMN, four of which encode chaperones:DNAJB2, which encodes a member of the HSP40/DNAJ co-chaperone family; andHSPB1, HSPB3, andHSPB8, encoding three members of the small heat shock protein family. While around 30 different mutations inHSPB1have been identified, the remaining three genes are altered in many fewer cases. Indeed, a mutation ofHSPB3has only been described in one case, whereas a few cases have been reported carrying mutations inDNAJB2andHSPB8, most of them caused by a founder c.352+1G>A mutation inDNAJB2and by mutations affecting the K141 residue in the HSPB8 chaperone. Hence, their rare occurrence makes it difficult to understand the pathological mechanisms driven by such mutations in this neuropathy. Chaperones can assemble into multi-chaperone complexes that form an integrated chaperone network within the cell. Such complexes fulfill relevant roles in a variety of processes, such as the correct folding of newly synthesized proteins, in which chaperones escort them to precise cellular locations, and as a response to protein misfolding, which includes the degradation of proteins that fail to refold properly. Despite this range of functions, mutations in some of these chaperones lead to diseases with a similar clinical profile, suggesting common pathways. This review provides an overview of the genetics of those dHMNs that share a common disease mechanism and that are caused by mutations in four genes encoding chaperones:DNAJB2, HSPB1, HSPB3, andHSPB8.
authors.affiliation: Molecular Basis of Human Diseases Program, Centro de Investigación Príncipe FelipeValencia, Spain; INCLIVA & IIS La Fe Rare Diseases Joint UnitsValencia, Spain.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lupo
authors.affiliation: Molecular Basis of Human Diseases Program, Centro de Investigación Príncipe FelipeValencia, Spain; INCLIVA & IIS La Fe Rare Diseases Joint UnitsValencia, Spain; Centro de Investigación Biomédica en RedValencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguado
authors.affiliation: Molecular Basis of Human Diseases Program, Centro de Investigación Príncipe FelipeValencia, Spain; INCLIVA & IIS La Fe Rare Diseases Joint UnitsValencia, Spain; Centro de Investigación Biomédica en RedValencia, Spain.
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
authors.affiliation: Molecular Basis of Human Diseases Program, Centro de Investigación Príncipe FelipeValencia, Spain; INCLIVA & IIS La Fe Rare Diseases Joint UnitsValencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Espinós
keywords: Chaperone; DNAJB2; Distal hereditary motor neuropathy; HSPB1; HSPB3; Heat shock protein; distal spinal muscular atrophy