Résumé :
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Distal hereditary motor neuronopathies form a heterogeneous group of rare inherited lower motor neuron disorders. Autosomal recessive inheritance has been reported in six subtypes (dHMN III, IV, VI, Jerash type). We studied a large inbred Israeli family of Moroccan ancestry composed of three affected and eight non-affected siblings. The disease was characterized by early adult onset and predominance of paralyses in the distal part of lower limbs. By homozygosity mapping strategy, we localized the disease gene in a 6,2 cM genetic interval on chromosome 2q35-2q36.1. In this region, we identified a homozygous point mutation in the sequence of gene DNAJB2. The mutation cosegregated with the disease in the family and was absent in 200 DNA controls. DNAJB2, or Heath Shock Protein DNAJ like 1(HSJ1), belongs to the DNAJ/HSP40 co-chaperone family. DNAJ/HSP40 are ATP-dependent positive regulators of HSP70 chaperon proteins, acting in the folding of protein substrates. Two main isoforms (DNAJB2-V1/HSJ1a and DNAJB2-V2/HSJb) are highly expressed in brain and spinal cord. Previous functional studies showed that DNAJB2 is involved in the ubiquitylation and the sorting of misfolded proteins to the ubiquitin proteasome system (UPS). The mutation reported here is responsible for an abnormal splicing of the DNAJB2 transcripts, causing retention of intron 4 and leading to a premature stop codon. Western blot analysis on patient's fibroblasts revealed a severe reduction of DNAJB2-V2 and the absence of DNAJB2-V1. Altered co-chaperone activity has been reported in many neurodegenerative diseases, including hereditary motor neuropathies (dHMNI and II) and animal models of motoneuron degeneration (Wobbler mouse). Recent studies highlighted the role of DNAJB2 in the reduction of intraneuronal aggregates in a cellular model of neurodegenerative disease (polyglutamine expansion) by increasing protein ubiquitylation and targeting to the UPS. Further functional studies will be required to understand the consequences of DNAJB2 defect on motor neuron degeneration process.
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