A novel gene, Doublecortin, expressed in the fetal brain and involved in certain malformations of the cerebral cortex, has just been identified by the Dr. Jamel Chelly's team at INSERM 129 (directed by Professor Axel Kahn, Paris, France). This should provide insight into how the brain develops and yield a tool for prenatal diagnosis in persons at risk. This work is published in Cell (January 9 th 1998).
In the early phases of embryonic development, the cerebral cortex is formed by the migration of successive waves of neurons. It is well established that defective neuronal migration can lead to severe cortical malformations, but the factors involved in this phenomenon are poorly understood. An interesting candidate is the Doublecortin gene, which has just been identified by Vincent des Portes and coworkers, who are part of the team headed by Dr. Jamel Chelly at INSERM 129 in Paris (directed by Professor Axel Kahn). In addition, the team showed that this gene is involved in some types of cortical malformations named the X-SCLH/LIS syndrome.
The X-SCLH/LIS syndrome was first described by French neuropaediatricians at Saint-Vincent de Paul hospital (Paris) and Reims, and is associated with severe forms of epilepsy and mental retardation. This syndrome consists of two similar malformations of the cerebral cortex known as subcortical laminar heterotopia (SCLH) and lissencephaly. The former is more common in girls, while the latter mainly affects boys. Subjects with this rare syndrome have an abnormally formed cortex.
The observation that the syndrome is exclusively transmitted by the mother, together with the severe forms affecting boys, pointed to sex-linked dominant genetic transmission.
The INSERM team first examined the hereditary transmission of genetic markers located on the sex chromosome X in members of three families in which girls had SCLH and boys had lissencephaly. This genetic mapping approach by linkage analysis allowed them to confirm that the defective gene responsible for the cortical malformations is located on the X chromosome. While sequencing the gene the team detected a point mutation in more than two-thirds of 17 patients with the X-SCLH/LIS syndrome, thereby demonstrating the major role of the Doublecortin gene in this disease condition.
Furthermore, the authors showed that Doublecortin was strongly expressed in the fetal brain, suggesting its implication in the early stages of cortical development.
The discovery of this gene has two important implications. First, it advances our understanding of the molecular mechanisms involved in brain development. Second, it provides a tool for prenatal diagnosis in persons at risk.
The work of INSERM 129 was done in collaboration with several hospital neuropaediatrics departments and a team from College de France. Technical support was provided by the Genethon and financial supports by the Fondation Jerome Lejeune and by Association Francaise contre les Myopathies thanks to Telethon. A patent application was submitted by INSERM on 21 November, 1997.
For more information :
" Identification of a novel CNS Gene Required for Neuronal Migration and involved in X-linked Subcortical Laminar Heterotopia and Lissencephaly syndrome " Vincent des Portes1 , Jean-Marc Pinard2 , Pierre Billuart1 , Marie-Claude Vinet1 , Annette Koulakoff3 , Alain Carriel1 , Antoinette Gelot4 , Elisabeth Dupuis5 , Jacques Motte6 , Yoheved Berwald-Netter3 , Martin Catala7 , Axel Kahn1 , Cherif Beldjord1 , and Jamel Chelly1
Cell, January 9th 1998
- INSERM 129-ICGM, Faculty of Medecine Cochin, Paris, France
- Neuropaediatrics unit, R. Poincare Hospital, Garches, France
- Cellular Biochemistry Laboratory, College de France, Paris, France
- Histo-embryology-cytogenetic Laboratory, Saint-Vincent de Paul Hospital, Paris, France
- Paediatrics unit, Louis Domergue Hospital, Trinite (Martinique), France
- Neuropaediatrics Duty, American Memorial Hospital, Reims, France
- Histo-embryology-cytogenetic Laboratory, La Pitie-Salpetriere Hospital, Paris,
France
###
Journal
Cell