title: A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation.
abstract: OBJECTIVE
  Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation.
  
  
  METHODS
  Homozygosity mapping strategy and sequencing of the candidate genes were performed. Expression studies were made on patient fibroblasts. Functional experiments were performed on a cellular model of motor neuron disease.
  
  
  RESULTS
  We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b. Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model.
  
  
  CONCLUSIONS
  HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. Previous studies have shown that HSP40 proteins play a crucial role in protein aggregation and neurodegeneration in several neuronal types, in animal models and human diseases. Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons.
authors.affiliation: Department of Neurology, Hillel Yaffe Medical Center, Hadera, Israel.
authors.forename: Sergiu C
authors.initials: SC
authors.lastname: Blumen
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Astord
authors.forename: Valérie
authors.initials: V
authors.lastname: Robin
authors.forename: Ludivine
authors.initials: L
authors.lastname: Vignaud
authors.forename: Nawel
authors.initials: N
authors.lastname: Toumi
authors.forename: Aurore
authors.initials: A
authors.lastname: Cieslik
authors.forename: Anat
authors.initials: A
authors.lastname: Achiron
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Carasso
authors.forename: Michael
authors.initials: M
authors.lastname: Gurevich
authors.forename: Itzhak
authors.initials: I
authors.lastname: Braverman
authors.forename: Nava
authors.initials: N
authors.lastname: Blumen
authors.forename: Arnold
authors.initials: A
authors.lastname: Munich
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.forename: Louis
authors.initials: L
authors.lastname: Viollet
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002874:Chromosome Mapping; D004576:Electromyography; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009018:Morocco; D016472:Motor Neuron Disease / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation; D010375:Pedigree; D055815:Young Adult
chemical_list: C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones