Genetics of mental retardation & cortical malformations

Our team

• About us...
• Composition
• Recent publications

Mental retardation

• Introduction
• Positional cloning
• Our work

Rett syndrome

• Introduction
• Clinical signs
• MeCP2 mutations
• Phenotypes
• Our work / Network

Cortical malformations

• Introduction
• Polymicrogyria
• Heterotopia
• Lissencephaly
• Classification
• Genetic causes
• Our work

Epilepsy

• The project
• Our work
• Call for collaboration

To read in august...

- Role of Olig1 and Olig2 in Down syndrome.

- TUBA1A mutations cause wide spectrum lissencephaly.

- Cell cloning-based transcriptome analysis in Rett patients.

Positional cloning - Mental retardation

Apparently balanced chromosomal rearrangements (translocations or inversions) associated to an abnormal phenotype have allowed to clone numerous disease genes.
The activity of the cytogenetics laboratory of the Timone children's hospital in Marseilles or the collaborations that we have established with foreign cytogenetics labs gave us several such balanced rearrangements associated with abnormal phenotypes, namely mental retardation. These rearrangements can be associated to a clinical symptomatology likely corresponding to a monogenic disease, a syndromic condition or to more complex clinical pictures. In each instance, mental retardation can be present.
We are performing physical mapping to localize the breakpoints, identify the molecular mechanism likely responsible for the abnormal phenotype and the mental retardation (deletion or duplication at the breakpoint or disruption of one or several genes).

Here are some examples of chromosomal rearrangements studied in our lab :

inv(X)(p22;q13) that lead to the cloning of the KIAA2022 gene in two patients with severe mental retardation. More recently, we have studied the expression of this gene during the development and shown that it is expressed in post-mitotic neurones and in specific brain regions after birth.

t(X;21) that lead to the cloning of the KLF8 gene in a female patient with moderate MR.

t(5;18) in a patient with moderate MR that we have studied with the laboratory of André Mégarbané in Lebanon and that lead us to study the region containing the FER gene in 5q21.3 (Haddad et al. 2009).

t(10;13) that lead to the cloning of the ATP8A2 gene in a patient with severe mental retardation. We studied the expression of the ATP8A2 gene and showed that it is specifically expressed in the central nervous system. The gene is broken by the chromosomal rearrangement. It is a good "candidate gene" to explain the phenotype of the studied patient (Cacciagli et al. 2010).

t(13;15) that lead to the cloning of a new gene (currently studied) in a patient with moderate MR.