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.


Contributing Members

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]

National and International Collaborations

Pr. Alain Taieb. [INSERM U1035 (Biothérapie des Maladies Génétiques Inflammatoires et Cancers, Bordeaux]
Dr. Isabelle Drumare-Bouvet | Dr Vasily Smirnov. [Service d’Exploration de la vision et de neuro-ophtalmologie, CHRU de Lille]
Dr. Sabine Defoort-Dhellemmes [Service d’Ophtalmologie, CHU de Bordeaux]
Dr Valentine Coste. [Institut Curie, Paris]
Dr. Cédric Delevoye. [MRC Human Genetics Unit, Edinburgh, UK]
Pr. Ian Jackson. [University of Pennsylvania, Philadelphia, USA]
Pr. Mickael Marks.

Project publications

Rooryck C, Roudaut C, Robine E, Müsebeck J, Arveiler B. Oculocutaneous Albinism Type 3 in a Caucasian Patient. Pigm Cell Res. 19, 239-242 (2006).

Rooryck C, Morice F, Mortemousque B, Lacombe L, Taïeb T, Arveiler B. Albinisme oculo-cutané. Revue générale. Ann Dermatol Vénérol. 134, 55-64 (2007).

Rooryck C., Morice-Picard F, Elçioglu NH., Lacombe D, Taieb A, Arveiler B. Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1 4 genes and practical aspects. Pigm Cell Melan Res (2008), 21:583-587.

Rooryck C, Morice-Picard F, Lacombe D, Taieb A, Arveiler B. Genetic basis of oculocutaneous albinism. Expert Rev. Dermatol., (2009) 4, 611-622.

Rooryck C, Morice-Picard F, Lasseaux E, Cailley D, Dollfus H, Defoort-Dhellemme S, Duban-Bedu B, de Ravel TJ, Taieb A, Lacombe D, Arveiler B. High resolution mapping of OCA2 intragenic rearrangements and identification of a founder effect associated with a deletion in Polish albino patients. Hum Genet (2011) 129:199–208.

Bocquet B, A Lacroux, M-O Surget, C Baudoin, V Marquette, G. Manes, M. Hebrard, A Sénéchal, A-F Roux, C.-M. Dhaenens, D. Allorge, J-M Rozet, I Perrault, J-P Bonnefont, J. Kaplan, H. Dollfus, P. Bonneau, I Audo, C Zeitz, V Paquis, P. Calvas, B. Arveiler, S. Kohl, B. Wissinger, C. Blanchet, I. Meunier, C. Hamel. Prevalence of inherited retinal dystrophies and optic neuropathies in Southern France: assessment from a 21-year data management. Ophthalmic Epidemiology, 2013;20:13-25.

Morice-Picard F, Lasseaux E, François S, Simon D, Rooryck C, Bieth E, Colin E, Bonneau D, Journel H, Walraedt S, Leroy B, Meire F, Lacombe D, Arveiler B. SLC24A5 mutations are associated with non-syndromic oculocutaneous albinism. J. Invest. Dermatol, 2014, 134:568-571.

Morice-Picard F, Lasseaux E, Cailley D, Gros A, Toutain J, Plaisant C, Simon D, François S, Gilbert-Dussardier B, Kaplan J, Rooryck C, Lacombe D, Arveiler B. High resolution array-CGH in patients with oculocutaneous albinism identifies new deletions of the TYR, OCA2 and SLC45A2 genes, and a complex rearrangement of the OCA2 gene. Pigm. Cell Melan. Res., 2014, 27:59-71

Montoliu L, Grønskov K, Wei AH, Martínez-García M, Fernández A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg T, Li W. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melan. Res. 2014, 27:11-18.

Bertolotti A, Lasseaux E, Plaisant C, Trimouille A, Morice-Picard F, Rooryck C, Lacombe D, Couppie P, Arveiler B. Identification of a homozygous mutation of SLC24A5 (OCA6) in two patients with oculocutaneous albinism from French Guiana. Pigment Cell Melanoma Res. 2016, 29:104-106.

Morice-Picard F, Lasseaux E, Plaisant C, Cailley D, Bouron J, Rooryck C, Lacombe D, Pelletier V, Lipsker D, Perdomo-Trujillo Y, Dollfus H, Arveiler B. Albinism in a patient with mutations at both the OA1 and OCA3 loci. Pigment Cell Melanoma Res. 2016, 29:107-109.

Goldman-Levy G, de la Fouchardiere A, Hamel CP, Lasseaux E, Yordanova Y, Guillot B, Bessis D, Pernet C, Frouin E, Boulle N, Haddad V, Pissaloux D, Costes V, Arveiler B, Rigau V. Primary leptomeningeal melanocytic tumour with a plaque-like blue nevus in a patient with ocular albinism. Eur J Dermatol. 2016, 26:496-498.

Morice-Picard F, Benard G, Rezvani HR, Lasseaux E, Simon D, Moutton S, Rooryck C, Lacombe D, Baumann C, Arveiler B. Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype. Eur J Hum Genet. 2016, 25:52-58.

Arveiler B, Lasseaux E, Morice-Picard F. Clinical and genetic aspects of albinism. Presse Med. 2017, 46:648-654.

Michaud V, Lasseaux E, Plaisant C, Verloes A, Perdomo-Trujillo Y, Hamel C, Elcioglu NH, Leroy B, Kaplan J, Jouk PS, Lacombe D, Fergelot P, Morice-Picard F, Arveiler B. Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS. Pigment Cell Melanoma Res. 2017, 30:563-570.

Marti A, Lasseaux E, Ezzedine K, Léauté-Labrèze C, Boralevi F, Paya C, Coste V, Deroissart V, Arveiler B, Taieb A, Morice-Picard F. Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting. Pigment Cell Melanoma Res. 2018 Mar 31(2):318-329.

Lasseaux E, Plaisant C, Michaud V, Pennamen P, Trimouille A, Gaston L, Monfermé S, Lacombe D, Rooryck C, Morice-Picard F, Arveiler B. Molecular characterization of a series of 990 index patients with albinism. Pigment Cell Melanoma Res., 2018, 31:466-474.

Monfermé S, et al., 2018 Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene. Br J Ophthalmol. 2018 Nov 24. pii: bjophthalmol-2018-312729.