A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation

Authors

  • Sergiu C. Blumen MD,

    1. Department of Neurology, Hillel Yaffe Medical Center, Hadera, Israel
    2. Rappaport Faculty of Medicine, Technion, Haifa, Israel
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    • S.C.B. and S.A., M.B. and L.V. contributed equally to this work.

  • Stéphanie Astord BSc,

    1. UPMC-AIM UMR S974, INSERM U 974, CNRS UMR 7215, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, France
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    • S.C.B. and S.A., M.B. and L.V. contributed equally to this work.

  • Valérie Robin PhD,

    1. UPMC-AIM UMR S974, INSERM U 974, CNRS UMR 7215, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, France
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  • Ludivine Vignaud BSc,

    1. Genethon, Evry, France
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  • Nawel Toumi BSc,

    1. Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, INSERM U781, Université Paris Descartes Paris 5, Paris, France
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  • Aurore Cieslik BSc,

    1. Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, INSERM U781, Université Paris Descartes Paris 5, Paris, France
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  • Anat Achiron MD PhD,

    1. Multiple Sclerosis Unit, Sheba Medical Center, Tel Hashomer, Israel
    2. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Ralph L. Carasso MD,

    1. Department of Neurology, Hillel Yaffe Medical Center, Hadera, Israel
    2. Rappaport Faculty of Medicine, Technion, Haifa, Israel
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  • Michael Gurevich PhD,

    1. Multiple Sclerosis Unit, Sheba Medical Center, Tel Hashomer, Israel
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  • Itzhak Braverman MD,

    1. Rappaport Faculty of Medicine, Technion, Haifa, Israel
    2. Otorhinolaryngology Unit, Hillel Yaffe Medical Center, Hadera, Israel
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  • Nava Blumen MD,

    1. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    2. Department of Neurological Rehabilitation, Sheba Medical Center, Tel Hashomer, Israel
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  • Arnold Munich MD, PhD,

    1. Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, INSERM U781, Université Paris Descartes Paris 5, Paris, France
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  • Martine Barkats PhD,

    1. UPMC-AIM UMR S974, INSERM U 974, CNRS UMR 7215, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, France
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    • S.C.B. and S.A., M.B. and L.V. contributed equally to this work.

  • Louis Viollet MD, PhD

    Corresponding author
    1. Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, INSERM U781, Université Paris Descartes Paris 5, Paris, France
    Current affiliation:
    1. Department of Neurology. University of Utah, Salt Lake City, UT, 84132
    • University of Utah. 30 North 1900 East SOM 3R149, Salt Lake City, UT 84132
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    • S.C.B. and S.A., M.B. and L.V. contributed equally to this work.


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.

Interpretation:

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. ANN NEUROL 2012;

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