Genetics in Ophthalmology
- Isabelle Perrault
- Josseline Kaplan
- Lucas Fares Taie
- Xavier Gérard
- Sophie Valleix
- Sylvie Gerber
- Iris Barny
- Cyril Burin-des-Roziers
- Alexandra Mouallem
- Mickael Soussan
- Brigitte Nedelec
Gerber S. Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome. Am J Hum Genet. 2016 May 5;98(5):971-80
Gérard X. Intravitreal Injection of Splice-switching Oligonucleotides to Manipulate Splicing in Retinal Cells. Mol Ther Nucleic Acids. 2015 Sep 1;4:e250.
Fares-Taie L. Submicroscopic deletions at 13q32.1 cause congenital microcoria. Am J Hum Genet. 2015 Apr 2;96(4):631-9.
PERRAULT I Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations Am J Hum Genet 2012 90(5):864-70
PERRAULT I Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy Nat Genet 2012 44(9):975-7
Genetics in Ophthalmology
In the late 80's, the first team of research dedicated to genetics of eye disorders in France settled in Paris at the Enfants-Malades Hospital.
For two decades, the team Genetics in Ophthalmology devoted its research to inherited retinal disorders which frequency and severity justify efforts made to characterize their molecular and physipathological bases, and to develop treatment protocols.
In close collaboration with the Department of Ophthalmology which is also the national “Referent Centre for Rare Diseases in Ophthalmology”, and with the contribution of National Departments of Genetics and Ophthalmology, nearly 2,500 families with detailed clinical data have been ascertained.
In early 90’s, epidemiological studies were performed, providing a clinical and genetic classification of retinal dystrophies in France and allowing the constitution of homogeneous cohorts of affected families.
Between 1993 and 2013, the team Genetics in Ophthalmology mapped and/or identified major genes for early-onset severe retinal dystrophies, including Usher syndrome type 1 (USH), Stargardt disease (STGD, Leber congenital amaurosis (LCA), pseudo-dominant X-linked retinitis pigmentosa (DXLRP), non-syndromic hereditary optic neuropathy (HON) and more recently eye dysgeneses. Joint analyses of genetic, molecular and detailed clinical data led on several occasions to modifications, or even radical changes, in the nosologic definition of some of these disorders, and to corollary changes in medical and genetic management of patients**.
The clinical delineation and genetic deciphering of Leber congenital amaurosis, non-syndromic optic neuropathies, and eye dysgeneses continue actively.
Leber congenital amaurosis is the leading cause of blindness in childhood. The two-decades long research of the group contributed to make from that disease the extreme example of the clinical, genetic and physiopathological heterogeneity of retinal dystrophies with: two phenotypic subtypes, 18 genes accounting for ca. 70% of cases, five metabolic pathways including intraflagellar transport (IFT) and neuroprotection, and a genetic overlap between non syndromic and syndromic forms of the disease. An exceptional sample of families is available at the Enfants-Malades Hospital. A hundred of these families have excluded all known disease-causing genes. This latter cohort of families constitutes a highly valuable tool to uncover missing LCA genes. Owing to the tremendous diversity of LCA genes function and tissular pattern of expression, OMICs analyses and high throughput sequencing will be favored to candidate gene strategies to identify novel LCA genes. In conjunction with this research program, the group leads a National Clinical Research Program (PHRC) whose main objective is to draw charters and recommendations for the long-term care and follow-up of genotyped patients.
Hereditary optic neuropathies (HONs) are primary causes of optic nerve degradation. They are characterized by a gradual loss of retinal ganglion cells (RGCs) and optic nerve axons leading to optic atrophy and ultimately to blindness. Mitochondria dysfunction has been reported to be a major cause of syndromic HONs; it is estimated that ON occurs in approximately 50% of mitochondrial disorders. The results of the Laboratory have highlighted that mitochondrial dysfunction is also a hallmark of nonsyndromic HONs and that, consistently, nonsyndromic HON are occasionally associated with silent to severe neurologic, muscular and/or neuromuscular deficits. More interestingly, the most recent work of the Laboratory has revealed, in collaboration with Agnès Rotig (Genetics of Mitochondrial Diseases ) and Nathalie Boddaert (Molecular Basis and Pathophysiology of Intellectual Disabilities), that there exist a genetic overlap between non syndromic and syndromic HON. The identification of three genes* which mutations cause either forms which support that this might not be exceptional should prompt a change in the follow-up of patients affected with HON. High energy-demanding organs including brain, heart, muscle and cochlea should be systematically examined to clarify the nosological definition of these disorders. This, in addition to the continuation of the genetic deciphering of HON using OMICs and next generation sequencing approaches, are major projects of the Laboratory for the years to come.
Finally, very recently the Laboratory has chosen to extend its research activities to a group of severe blinding conditions due to inborn errors of eye development. First very promising results have been obtained with the identification of a direct link between the synthesis of retinoic acid and embryonic development of the eyeball and that of a gene involved in smooth muscle differentiation which mutations cause congenital microcoria.