S.C.B. and S.A., M.B. and L.V. contributed equally to this work.
A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation
Article first published online: 20 APR 2012
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 4, pages 509–519, April 2012
How to Cite
Blumen, S. C., Astord, S., Robin, V., Vignaud, L., Toumi, N., Cieslik, A., Achiron, A., Carasso, R. L., Gurevich, M., Braverman, I., Blumen, N., Munich, A., Barkats, M. and Viollet, L. (2012), A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. Ann Neurol., 71: 509–519. doi: 10.1002/ana.22684
- Issue published online: 20 APR 2012
- Article first published online: 20 APR 2012
- Accepted manuscript online: 27 NOV 2011 11:11PM EST
- Manuscript Accepted: 18 NOV 2011
- Manuscript Revised: 15 OCT 2011
- Manuscript Received: 28 MAY 2010
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.
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.
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.
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;