Jean-Louis Mandel, born in Strasbourg on February 12, 1946, is a French medical doctor and geneticist, and heads a research team at the Institute of Genetics and Molecular and Cellular Biology (IGBMC). He has been in charge of the genetic diagnosis laboratory at the University Hospitals of Strasbourg since 1992, as well as a professor at the Collège de France (Chair of Human Genetics) since 2003.
Doctor of Medicine (1971) and Doctor of Science (1974) from the University of Strasbourg (theses prepared under the supervision of Prof. Pierre Chambon), Jean-Louis Mandel was Associate Professor of Biochemistry at the Faculty of Medicine of the University of Strasbourg from 1978 to 1984, then Professor of Medical Genetics at the same Faculty from 1984 to 2003 before being appointed to the Chair of Human Genetics at the Collège de France. He leads a research team in human genetics at the LGME (Laboratoire de Génétique Moléculaire des Eucaryotes, directed by Pierre Chambon) which became the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in 1994. He started a molecular diagnosis of genetic diseases in 1985, which became the genetic diagnosis laboratory at the University Hospitals of Strasbourg in 1992, for which he has been responsible since then. Jean-Louis Mandel was appointed Director of the Institute of Genetics and Molecular and Cellular Biology (IGBMC) from 2002 to 2007, following its founder Pierre Chambon, then Deputy Director from 2007 to 2009. From 2008 to 2009, he was Director of the Mouse Clinic (ICS). He has also been a full member of the French Academy of sciences since 1999 [1] and a corresponding member of the French Academy of Medicine.
Since 1982, Jean-Louis Mandel has been working on the identification of genes and mutations responsible for rare inherited monogenic diseases affecting the nervous system and/or muscles. He has also contributed to the development of diagnostic tests and the analysis of pathophysiological mechanisms for several of these diseases, using animal or cellular models in particular. His most important contribution concerns the identification and characterization of the mutation mechanism by unstable expansion of trinucleotide repetition. In 1991, his team showed that Fragile X mental retardation syndrome, the most common cause of hereditary intellectual disability, is due to the expansion of a CGG repetition associated with localized abnormal DNA methylation (Oberlé et al. Sciences, 1991). From 1995 to 1997 his team (with notably Yvon Trottier), in collaboration with Alexis Brice's team (Hôpital Pitié Salpétrière) identified polyglutamine expansions as pathogenic epitopes in Huntington's disease and four other dominant ataxias, which led to the identification of genes involved in the spinocerebellar ataxias SCA2 and SCA7 (Trottier et al, Nature, 1995, Imbert et al. Nat Genet 1996, David et al. Nat Genet 1997). In 1996, with Michel Koenig and Massimo Pandolfo, he showed that Friedreich's Ataxia, a neurodegenerative disease, is caused by the expansion of a GAA repetition in the gene encoding a protein of unknown function, frataxin, and participates in clinical and genetic studies on this disease (Dürr et al, NEJM, 1996). Jean-Louis Mandel has also identified the genes responsible for adrenoleukodystrophy, with Patrick Aubourg (Mosser et al, Nature, 1993), ataxia with isolated vitamin E deficiency with Michel Koenig (Ouahchi et al, Nature Genetics, 1995), Coffin-Lowry syndrome (mental retardation linked to chromosome X) with André Hanauer (Trivier et al, Nature, 1996). His work with Jocelyn Laporte has led to the identification of the mutated MTM1 gene in X-linked myotubular myopathy (Laporte et al Nat Genet 1996) and more recently the mutated BIN1 gene in autosomal recessive centronuclear myopathy (Nicot et al, Nature Genet, 2007). For several years, Jean-Louis Mandel has concentrated a significant part of his activity on the development of effective strategies for the molecular diagnosis of monogenic intellectual deficiencies, which affect more than 1% of the population and are characterized by extreme genetic heterogeneity, and for a better clinical knowledge of these different genetic forms (projet GenIDA [2] [archive]) (Piton et al, AJHG, 2013, and Redin et al. J Med Genet 2014).
J.L. Mandel has published more than 350 articles and has an H-index of 86 (Web of Science, January 2015). Below, about thirty representative publications (* publications cited more than 200 times, ** more than 500 times)
Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.
FMR1 is a human gene that codes for a protein called fragile X messenger ribonucleoprotein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits. The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.
Centronuclear myopathies (CNM) are a group of congenital myopathies where cell nuclei are abnormally located in the center of muscle cells instead of their normal location at the periphery.
Alpha-thalassemia mental retardation syndrome (ATRX), also called alpha-thalassemia X-linked intellectual disability syndrome, nondeletion type or ATR-X syndrome, is an X-linked recessive condition associated with a mutation in the ATRX gene. Males with this condition tend to be moderately intellectually disabled and have physical characteristics including coarse facial features, microcephaly, hypertelorism, a depressed nasal bridge, a tented upper lip and an everted lower lip. Mild or moderate anemia, associated with alpha-thalassemia, is part of the condition. Females with this mutated gene have no specific signs or features, but if they do, they may demonstrate skewed X chromosome inactivation.
A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum, is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections. To date, about 50 cases have been reported.
Brunner syndrome is a rare genetic disorder associated with a mutation in the MAOA gene. It is characterized by lower than average IQ, problematic impulsive behavior, sleep disorders and mood swings. It was identified in fourteen males from one family in 1993. It has since been discovered in additional families.
Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein (XNP) is a protein that in humans is encoded by the ATRX gene.
Myotubularin is a protein that in humans is encoded by the MTM1 gene.
Fragile X mental retardation syndrome-related protein 2 is a protein that in humans is encoded by the FXR2 gene.
X-linked intellectual disability refers to medical disorders associated with X-linked recessive inheritance that result in intellectual disability.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. The main clinical features of FXTAS include problems of movement with cerebellar gait ataxia and action tremor. Associated features include parkinsonism, cognitive decline, and dysfunction of the autonomic nervous system. FXTAS is found in Fragile X "premutation" carriers, which is defined as a trinucleotide repeat expansion of 55-200 CGG repeats in the Fragile X mental retardation-1 (FMR1) gene. 4-40 CGG repeats in this gene is considered normal, while individual with >200 repeats have full Fragile X Syndrome.
Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency, is a rare genetic disorder. The disorder is characterized by partial aniridia, ataxia, and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.
Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as Marfanoid habitus, referring to a group of physical characteristics similar to those found in Marfan syndrome. These features include a tall, thin stature and long, slender limbs. LFS is also associated with psychopathology and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart. The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the MED12 gene. There is currently no treatment or therapy for the underlying MED12 malfunction, and the exact cause of the disorder remains unclear.
Hennekam syndrome also known as intestinal lymphagiectasia–lymphedema–mental retardation syndrome, is an autosomal recessive disorder consisting of intestinal lymphangiectasia, facial anomalies, peripheral lymphedema, and mild to moderate levels of growth and intellectual disability.
Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is the most common genetic cause of premature ovarian failure in women with a normal karyotype 46, XX. The expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene from the normal range of 5-45 repeats to the premutation range of 55-199 CGGs leads to risk of FXPOI for ovary-bearing individuals. About 1:150-1:200 women in the US population carry a premutation. Women who carry an FMR1 premutation have a roughly 20% risk of being diagnosed with FXPOI, compared to 1% for the general population, and an 8-15% risk of developing the neurogenerative tremor/ataxia disorder (FXTAS). FMR1 premutation women are also at increased risk of having a child with a CGG repeat that is expanded to >200 repeats. Individuals with a full mutation, unlike the premutation, produce little to no mRNA or protein from the FMR1 gene and are affected with Fragile X syndrome.
Robert Williamson is a retired British-Australian molecular biologist who specialised in the mapping, gene identification, and diagnosis of human genetic disorders.
David L. Nelson is an American human geneticist, currently an associate director at the Intellectual and Developmental Disabilities Research Center (1995), and professor at the Department of Molecular and Human Genetics at Baylor College of Medicine BCM since 1999. Since 2018, he is the director at the Cancer and Cell Biology Ph.D program, and the director of Integrative Molecular and Biomedical Sciences Ph.D since 2015 at BCM.
| International | |
|---|---|
| National | |
| Academics | |
| Other | |
