High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features.

Gaël Manes (1) , Tremeur Guillaumie (2) , Werner L Vos (3) , Aurore Devos (4) , Isabelle Audo (5) , Christina Zeitz (5) , Virginie Marquette (1, 2) , Xavier Zanlonghi (6) , Sabine Defoort-Dhellemmes (7) , Bernard Puech (7) , Saddek Mohand Said (5) , José-Alain Sahel (5) , Sylvie Odent (8) , Hélène Dollfus (9) , Josseline Kaplan (10) , Jean-Louis Dufier (11) , Guylène Le Meur (12) , Michel Weber (12) , Laurence Faivre (13) , Francine Behar Cohen (11) , Christophe Béroud (14) , Marie-Christine Picot (15) , Coralie Verdier (1) , Audrey Sénéchal (1) , Corinne Baudoin (2) , Béatrice Bocquet (1, 2) , John B Findlay (3) , Isabelle Meunier (1, 2) , Claire-Marie Dhaenens (4) , Christian P Hamel (1, 2)

1 INM - Institut des Neurosciences de Montpellier
2 Genetics of Sensory Diseases
3 The Marie Curie Laboratory for Membrane Proteins
4 UF Génopathies - UF Génopathies, Pharmaco-génétique, Glycobiologie et Dépistage Périnatal
5 Institut de la Vision
6 Clinique Sourdille
7 LNFP - Laboratoire de Neurosciences Fonctionnelles et Pathologies
8 IGDR - Institut de Génétique et Développement de Rennes
9 Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale
10 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
11 Service d'ophtalmologie [CHU Necker]
12 Service d'ophtalmologie [Nantes]
13 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
14 GMGF - Génétique Médicale et Génomique Fonctionnelle
15 Clinical Investigation Centre

PURPOSE:To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report six novel mutations, to characterize the biochemical features of a recurrent novel mutation and to study the clinical features of adRP patients.DESIGN:Retrospective clinical and molecular genetic study.METHODS:Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.RESULTS:We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1 to 0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.CONCLUSIONS:The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases which could be underdiagnosed.

Domaines: Organes des sens

Gaël Manes, Tremeur Guillaumie, Werner L Vos, Aurore Devos, Isabelle Audo, et al.. High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features.. Ophthalmology: Journal of The American Academy of Ophthalmology, 2015, 159 (2), pp.302-314. ⟨10.1016/j.ajo.2014.10.033⟩. ⟨hal-01091447⟩