Florence Molinari Identification and functional study of genes involved in Neurodevelopmental diseases

Course and current status


From 2019     Researcher, permanent position (CRCN INSERM), in Nicolas Lévy’s Laboratory: “Human Neurogenetics”, Marseille Medical Genetics (MMG), Faculté de Médecine de la Timone (Marseille, France)

2009-2019           Researcher, permanent position (CR1 INSERM), in Alfonso Represa’s Laboratory: “Neonatal epileptic encephalopathies and glutamate transporters”, INMED, Parc Scientifique de Luminy (Marseille, France)

2006-2008            Researcher, permanent position (CR2 INSERM), in Arnold Munnich’s Laboratory: “Identification and functional analysis of genes involved in autosomal recessive form of mental retardation”, Hôpital Necker-Enfants Malades (Paris, France).

2005                   Post-doctoral position in Peter Sonderegger’s Laboratory, “Behavioural Studies of Prss12 KO Mice”, Institute of Biochemistry, Zürich University (Switzerland).     

2001-2004          Ph. D in Genetics, defended November 25th 2004: “Identification and functional analysis of genes involved in autosomal recessive form of mental retardation”, headed by Laurence Colleaux, Hôpital Necker-Enfants Malades (Paris, France).

Scientific background

CRCN-MMG       The aim of project at MMG is to identify new genes involved in neurodevelopemental diseases, mainly intellectual deficiency, and to perform functional analysis in order to figure out their pathophysiology. These studies will also help us to better understand the development of cognitive functions in humans.

CR1 -INMED           The aim of my project at INMED was to understand the mechanisms involved in neonatal epileptic encephalopathy, more precisely in SLC25A22 and KCNQ2-related encephalopathies. I gained experience in glial cells culture and transfection and electrophysiology techniques such as patch clamp and field recordings.

CR2 INSERM            The aim of my first position was to identify genes involved in autosomal recessive form of mental retardation. I succeed to identify mutations in two genes, TUSC3 (11p15.5) and IAP (Xq22), which are involved in the same pathway: the N-glycosylation. I gained experience in quantitative RT-PCR and RNA interference.

Post-doctorate      The aim of my post-doctorate is to characterized Prss12 mice using cognitive tests. I perform these tests in collaboration with David P. Wolfer and Hans P. Lipp. I gain experiments in cognitive tests such as Water Maze, Open Field, Radial Maze, Object Intrusion, Light-Dark Box, Puzzle Box, Rotarod, and Startle. I also learned neuronal (low and high density) and glial cells cultures for immunolocalization.

Ph D                          The aim of my thesis was to identify new genes involved in autosomal recessive form of mental retardation using homozygosity mapping and inbred families. This work resulted in the identification and the functional analysis of two genes: PRSS12 involved in an autosomal recessive nonsyndromic mental retardation, and SLC25A22 involved in a mental retardation associated with a severe neonatal epileptic encephalopathy. I gained experience in a number of techniques such as PCR, RT-PCR, genotyping, sequencing, Northern hybridization, in-situ Hybridization, mutation detection with DHPLC and computer aided gene database analysis.

Academic and Professional Awards

2008           Isabelle Oberlé Award, European Society of Human Genetics meeting

2005            Fellowship from Fondation de la Recherche Médicale

2002           Isabelle Oberlé Award, European Society of Human Genetics meeting

2001-2004 Fellowship from the French Ministry of Research

Scientific summary

Intellectual Disability (ID) is the most common major handicap in children and young adults and affects nearly 3% of the general population. Intellectual disability is a disorder characterized by significant limitations in both intellectual functioning and in adaptive behavior, which covers many everyday social and practical skills. According to the World Health Organization (WHO)’s recommendations, a simplified classification based on the intelligence quotient (IQ) defines two groups of ID: Mild ID for an IQ between 50 and 70 and severe ID for an IQ below 50. Many dysfunctions may be associated with ID, such as dysmorphia, neurodevelopmental disorders or psychopathological disorders; this is referred to as syndromic ID, such as the Angelman or X-fragile syndromes. In the case where ID is not associated with any other clinical anomaly, it is called isolated or non-syndromic ID (NSID). The causes of these disorders are very diverse (environmental or genetic) and despite great progress in cytogenetics and molecular biology, particularly with the development of high-throughput sequencing, nearly 40% of cases still remain unexplained, mainly in the case of NSID. The importance of these diseases in terms of public health and the complexity of the biological processes involved make understanding the pathophysiological basis of ID one of the major scientific and medical challenges of the coming years. Moreover, identification of the causes of these conditions, in particular those of NSID, will allow us to better understand the mechanisms involved in the development of the central nervous system (CNS) and the establishment of cognitive functions in humans. These studies are essential to identify the role of defective proteins in patients and thus to develop new therapeutic approaches.

The Marseille Medical Genetics Center (MMG, INSERM U1251) works in close collaboration with the clinicians of the Timone hospital’s medical genetics and pediatric neurology departments. Taking advantages of this fruitful collaboration, the Human Neurogenetics team has begun to set up a cohort of patients with ID associated or not with other clinical signs. This cohort currently includes about twenty families for whom a series of tests have been performed, in at least one of the affected members, in order to better characterize the disease: a detailed clinical examination with multiple analyses including high resolution karyotype, CGH-array, metabolic and molecular tests (X-Fragile, Angelman) and a targeted sequencing for a panel of genes known to be involved in ID has been performed. If, despite all these analyses, no diagnosis is established, then our research team proposes to carry out a Whole Exome Sequencing (WES) for both parents and one of the affected children. WES is a powerful technique for sequencing all of the coding regions of the genes, constituting about 2% of the whole human genome. This technique significantly increases the rate of diagnosis, particularly in the case of patients with rare or isolated diseases such as NSID. This strategy, that has been used by our team since 2017, is highly effective since we have been able to identify a candidate gene for 9 families among 15 analyzed, i.e. 60% of the studied families. Then, in order to properly associate this gene to the pathology, functional analyses are needed.

The project that I manage at MMG has a dual objective: (i) Improve the analysis of the so-called "negative" families by developing new bioinformatics tools and (ii) Characterize the role and function of the proteins identified by our team.

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