Guy LENAERS Principle Investigator

Course and current status

PhD in 1990, HDR in 2003.

Group Leader on Inherited Optic Neuropathies and Mitochondrial Deficits in the team Genetics and Therapies of retinal and optic nerve blindness, at the Institut des Neurosciences de Montpellier, U1051 of INSERM, headed by Pr Christian HAMEL

Scientific summary

The non-syndromic hereditary optic neuropathies, including primarily the Dominant Optic Atrophy (DOA, prevalence 1/20 000) and the Leber Hereditary Optic Neuropathy (LHON, prevalence 1/30 000) are leading causes of hereditary blindness in Western countries. They are characterized by a degenerative process of the retinal ganglion cells (RGCs), with consequently a loss of the optic nerve fibers leading to the impairment of the visual transduction from the retina to the brain. Today, there is no treatment to prevent the progress of the degenerative process. DOA, which is the subject of our investigations, is clinically characterized by progressive bilateral loss of the central visual field and vision colors, and the presence of papilla pallor at eye examination, without other retinal alteration. At OCT patients present a significant reduction of the retinal nerve fiber layer, mainly at the optic papilla. Electrophysiological measurements evidence a significant decrease of visual evoked potential (VEP) and the maintenance of electroretinogram (ERG), reflecting a specific functional impairment of the optic nerve (Delettre et al., 2002; Hamel and Lenaers, 2007).

Eight loci responsible of Optic Atrophy have been identified, 5 for of a dominant form (OPA1, 3, 4, 5 and 7), two for a recessive form (OPA6, OPA7 or ROA1, ROA2) and one associated to chromosome X (OPA2). To date, only three genes are known, (OPA1, OPA3 and OPA7 or TMEM126A), all encoding proteins associated to the inner mitochondrial membrane (Delettre et al., 2000; Hanein et al., 2009; Olichon et al., 2002; Reynier et al., 2004, Lenaers et al., 2012), as the ND1, ND4 et ND6 proteins, encoded by the mitochondrial genome, which are mutated in LHON. The convergence of all these protein localization set inherited optic neuropathies among mitochondrial diseases (Delettre et al., 2002; Lenaers et al., 2012).

OPA1 is the major gene of DOA, representing approximately 70 % of non-syndromic patients with genetic diagnosis. OPA1 encodes a mitochondrial dynamin localized in the inter membrane space of mitochondria (Olichon et al., 2002). Fundamental studies on HeLa cells and pathophysiological studies on a collection of patient fibroblasts showed that OPA1 functions concern the dynamics of the mitochondrial network, the membrane potential maintenance, the cell respiration, the apoptotic process and the maintenance of the mitochondrial genome (Amati-Bonneau et al., 2005; Chevrollier et al., 2008; Kamei et al., 2005; Olichon et al., 2003; Olichon et al., 2007b; Elachouri et al., 2011). These different functions are associated with singular OPA1 isoforms, resulting from alternative splicing of exons 4, 4b and 5b (Olichon et al., 2007a, Elachouri et al., 2011). Despite the accumulation of knowledge about OPA1 functions, it is still not known which one is limiting and responsible for the RGC death. Nevertheless, in OPA1 non-syndromic patient fibroblasts, as well as in Opa1+/- mouse models, it has been clearly demonstrated that OPA1 expression levels are systematically 50% reduced (Sarzi et al. 2012), suggesting that the mutated allele is counter-selected and that OPA1 haplo-insufficiency, although well tolerated in other cell types of the body (absence of secondary clinical symptom in most patients), represents the central and princeps mechanism of DOA pathophysiology.

 

Major achievements:

- Identification of OPA1 as the principal gene responsible for Dominant Optic Atrophy (DOA, Delettre, 2000 and 2001)

- Localisation of OPA1 in the mitochondria (Olichon 2002)

- First characterization of OPA1 functions in mitochondrial dynamics, cristae structure and apoptosis (Olichon, 2003)

- Contribution to the discovery of mutations in OPA3 gene in DOA + cataract. (Reynier 2004)

- Contribution to the characterisation of the first syndromic DOA patients (Amati-Bonneau, 2005)

- Characterization of DOA pathophysiology (Kamei, 2005, Olichon, 2007)

- Characterization of the function of OPA1 isoforms and cleavage (Olichon, 2007; Baricault 2007)

- Identification of the genetic basis of a reversible form of DOA (Cornille, 2008)

- Participation to a multi-centric analysis of syndromic DOA patients (Amati-Bonneau, 2008)

- Characterization of OPA1 function in calcium clearance in retinal ganglion cells (Dayanithi, 2010)

- Characterization of OPA1 involvement in mitochondrial genome maintenance (Elachouri, 2011)

- Characterization of Opa1 (Sarzi, 2012) and Wfs1 (Bonnet in prep) mouse models.

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