Search for missing mutations in patients with albinism
Albinism is a clinically and genetically heterogeneous condition characterized by variable degrees of hypopigmentation (extending from a complete absence of pigmentation to a normal pigmentation) and by ophthalmological anomalies including reduced visual acuity, chiasmatic misrouting of the optic nerves, nystagmus, foveal hypoplasia, iris transillumination, and retinal hypopigmentation, all leading to reduced visual acuity. 19 genes are involved in the oculocutaneous, ocular and syndromic (Hermansky-Pudlak Syndrome and Chediak-Higashi Syndrome) forms of the disease.
Our laboratory at University Hospital of Bordeaux has been performing the molecular diagnosis of albinism for more than 15 years. It is a reference laboratory at the national and international levels, being the only one in Europe to perform an extensive analysis of all 19 genes in order to identify both point mutation (next generation sequencing, NGS) and intragenic rearrangements (high resolution array-CGH). Our series of more than 1400 patients constitutes probably the largest cohort of patients with albinism worldwide.
Despite our extensive analyses, about 25% of the patients remain without a molecular diagnosis, because either only one or no mutation at all has been identified in the 19 known genes.
Our research program at INSERM U 1211 comprises:
1) Intensifying the analysis of the 19 known genes by looking for variants in the flanking genomic regions and in the introns. More specifically our aim is to search for pathogenic variants in the regulatory elements of the genes. These elements are largely unknown as yet. We shall identify them by a double approach combining bioinformatics analyses and Hi-C capture studies. The selected elements will be sequenced in the patients remaining without a molecular diagnosis. Functional tests will be undertaken in order to evaluate the variants’ pathogenicity.
2) Searching for new albinism genes, using a “candidate gene” strategy. 129 functional candidates involved in melanogenesis have been selected and were sequenced in about 200 patients. Two new genes have been identified so far. Functional studies are currently being performed, namely in cellular and animal (mouse, zebrafish) models, in order to validate these genes. This work will be continued in order to identify more genes.
3) Developing a new panel of genes (80-100 genes) for the differential diagnosis in patients presenting with an incomplete form of “ocular albinism “.
4) Functional validation of variants of unknown significance found during diagnostic process. These are essentially splicing, missense and synonymous variants.
This project is typically at the interface between healthcare and research and exemplifies the advantage of collecting large national and international cohorts of patients with rare diseases.
Benoit Arveiler [University Professor – Hospital Practitioner, Principal Investigator]
Perrine Pennamen [Hospital Practitioner, PhD Student]
Angèle Tingaud-Sequeira [Engineer]
Aurélien Trimouille [Hospital and University Assistant]
Christophe Hubert [Engineer]
Vincent Michaud [Resident]
Sophie Javerzat [University Professor]
National and International Collaborations
Pr. Alain Taieb. [INSERM U1035 (Biothérapie des Maladies Génétiques Inflammatoires et Cancers, Bordeaux]
Dr. Isabelle Drumare-Bouvet | Dr Vasily Smirnov | Dr. Sabine Defoort-Dhellemmes. [Service d’Exploration de la vision et de neuro-ophtalmologie, CHRU de Lille]
Dr. Fanny Morice-Picard [Service de Dermatologie, CHU de Bordeaux]
Dr Valentine Coste. [Service d’Ophtalmologie, CHU de Bordeaux]
Dr. Cédric Delevoye. [Institut Curie, Paris]
Pr. Ian Jackson. [MRC Human Genetics Unit, Edinburgh, UK]
Pr. Mickael Marks. [University of Pennsylvania, Philadelphia, USA]
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