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A new gene thought to be at cause in early-onset forms of Alzheimer’s disease

A new gene that causes early-onset of Alzheimer’s disease has been discovered by the research team of Dominique Campion at the Insert unit 1079 ”Genetics of cancer and neuropsychiatric diseases” in Rouen. The research scientists showed that in the families of 5 of 14 patients suffering from the disease, mutations were detected on the gene SORL1. This gene regulates the production of a peptide involved in Alzheimer’s disease. The results of this study have been published in the review Molecular Psychiatry issued April 3rd

Precise genetic mutations have been seen to play a part in early-onset forms of Alzheimer’s disease. However, there is a sub-population of patients in whom there is no mutation of these genes. So how can these patients, in whom there are no pre-established mutations, be suffering from early-onset Alzheimer’s?

To reply to this question, the research team working under the leadership of Dominique Campion and Didier Hannequin (Inserm unit 1079 and Centre national de référence malades Alzheimer jeunes, University hospital Rouen), studied the genes from 130 families suffering from early-onset forms of Alzheimer’s disease. These families were identified by 23 French hospital teams within the framework of the “Alzheimer Plan”. Of these families, 116 presented mutations on the already known genes. But in the 14 remaining families, there was no mutation at all observed on these genes.

A study of the genome of the 14 families using new whole DNA sequencing techniques showed evidence of mutations on a new SORL1 gene. The SORL1 gene is a coding gene for a protein involved in the production of the beta-amyloid peptide. This protein is known to affect the functioning of the brain cells (see insert).

Two of the identified mutations are responsible for an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. “The mutations observed on SORL1 seem to contribute to the development of early-onset Alzheimer’s disease. However, we still need to identify more clearly the way in which these mutations are transmitted on the SORL1 gene within families” states Dominique Campion.

Alzheimer’s disease is one of the main causes of dependency among the elderly. It results from neuron degradation in different areas of the brain. Its symptoms include increased alterations to memory, cognitive functions and behaviour disorders that lead to a progressive loss of independence.

Alzheimer’s disease is characterized by the development of two types of lesion in the brain: amyloid plaques and neurofibrillary degenerescence. Amyloid plaques are caused by extracellular accumulation of a peptide, beta-amyloid peptide (Aβ) in specific areas of the brain. Neurofibrillary degenerescences are intraneuronal lesions caused by abnormal filamentary aggregation of a protein known as a Tau protein.

Researcher Contact
Dominique Campion Co-responsable du Centre national de référence Alzheimer malades jeunes. Chercheur au sein de l’Unité Inserm 1079 « Génétique du cancer et des maladies neuropsychiatriques » 02 35 14 82 80 rf.neuor-vinu@noipmac.euqinimod
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High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease C. Pottier1,2, D. Hannequin1,2, S. Coutant1,2, A. Rovelet-Lecrux1,2, D. Wallon1,2, S. Rousseau1,2, S. Legallic1,2, C. Paquet3, S. Bombois2,4, J. Pariente5, C. Thomas-Anterion6, A. Michon2,7, B. Croisile8, F. Etcharry-Bouyx9, C. Berr10, J-F. Dartigues11, P. Amouyel12, H. Dauchel13, C. Boutoleau-Bretonnière14, C. Thauvin15, T. Frebourg1, J-C. Lambert12 et D. Campion1,2,16, PHRC GMAJ collaborators17 1Department of Molecular Genetics, Inserm U1079, Institute for Biomedical Research and Innovation, University of Rouen, Rouen, France; 2CNR-MAJ, Rouen University Hospital, Lille University Hospital and Paris Salpêtrière University Hospital, France; 3CMRR Nord, Inserm U839, Lariboisière University Hospital, Paris, France; 4EA1046, Lille Nord University Hospital, Lille, France; 5Department of Neurology, CMRR and Inserm U825, Purpan University Hospital, Toulouse, France; 6Department of Neurology, CMRR, University Hospital Nord, Saint Etienne, France; 7CRCICM, IM2A, UMR-S975 AP-HP, University Hospital Pitié-Salpêtrière, Paris, France; 8Department of Neuropsychology, CMRR, University Hospital, Groupe Hospitalier Est, Bron, France; 9Department of Neurology, Angers University Hospital, Angers, France; 10INSERM U888, Hôpital La Colombière, Montpellier, France; 11INSERM U897, Victor Segalen University, Bordeaux, France; 12INSERM U744, Pasteur Institute of Lille, Lille, France; 13LITIS, EA 4108, University of Rouen, Rouen, France; 14Department of Neurology, CMRR, Nantes University Hospital, Nantes, France; 15Department of Genetics, Dijon University Hospital, Dijon, France and Q2 16Le Rouvray Hospital, Sotteville les Rouen, France Molecular Psychiatry, le 03 avril, doi: 10.1038/mp.2012.15