SLC24A5 Mutations Are Associated with Non-Syndromic Oculocutaneous Albinism.

TO THE EDITOR Oculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by hypomelanosis of the skin, hair, and eyes, associated with reduced visual acuity, nystagmus, and photophobia (Tomita and Suzuki, 2004Tomita Y. Suzuki T. Genetics of pigmentary disorders.Am J Med Genet C Semin Med Genet. 2004; 131C: 75-81Crossref PubMed Scopus (121) Google Scholar). Its worldwide prevalence is approximately 1:17,000 (Witkop, 1979Witkop C.J. Albinism: hematologic-storage disease, susceptibility to skin cancer, and optic neuronal defects shared in all types of oculocutaneous and ocular albinism.Ala J Med Sci. 1979; 16: 327-330PubMed Google Scholar). Hypopigmentation or complete lack of pigmentation is caused by a deficiency involving the production, metabolism, or distribution of melanin, the main pigment responsible for skin coloration. Diagnosis is based on clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular symptoms. OCA can be isolated or associated with other anomalies in syndromic forms (Tomita and Suzuki, 2004Tomita Y. Suzuki T. Genetics of pigmentary disorders.Am J Med Genet C Semin Med Genet. 2004; 131C: 75-81Crossref PubMed Scopus (121) Google Scholar). Mutations of the TYR, OCA2, TYRP1, and SLC45A2 genes have been associated with non-syndromic forms of OCA (OCA1–4, respectively). As these four genes do not account for all non-syndromic OCA, it has long been hypothesized that other genes might be involved. To date, more than 125 genes have been involved in pigmentation regulation, and many of them (at least 25) affect the biogenesis or function of melanosomes. Several genes encoding melanosomal proteins including TYRP2, SLC24A5, SILV, RAB7, and RAB38 have been considered as good candidates for OCA. However, until recently, no pathological mutations of these genes had been reported in human OCA patients (Suzuki et al., 2003Suzuki T. Miyamura Y. Inagaki K. et al.Characterization of the human RAB38 and RAB7 genes: exclusion of new major pathological loci for Japanese OCA.J Dermatol Sci. 2003; 32: 131-136Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, Hutton and Spritz, 2008Hutton S.M. Spritz R.A. Comprehensive analysis of oculocutaneous albinism among non-Hispanic caucasians shows that OCA1 is the most prevalent OCA type.J Invest Dermatol. 2008; 128: 2442-2450Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, Grønskov et al., 2009Grønskov K. Ek J. Sand A. et al.Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism.Invest Ophthalmol Vis Sci. 2009; 50: 1058-1064Crossref PubMed Scopus (65) Google Scholar, Mondal et al., 2012Mondal M. Sengupta M. Samanta S. et al.Molecular basis of albinism in India: evaluation of seven potential candidate genes and some new findings.Gene. 2012; 511: 470-474Crossref PubMed Scopus (23) Google Scholar). Very recently, two new OCA genes were uncovered. Mutations of C10orf11 were identified in a family from the Faroe Islands and in a Lithuanian patient (Grønskov et al., 2013Grønskov K. Dooley C.M. Østergaard E. et al.Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.Am J Hum Genet. 2013; 92: 415-421Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), and mutations of SLC24A5 were found in a Chinese patient presenting with non-syndromic OCA (Wei et al., 2013Wei A-H. Zang D-J. Zhang Z. et al.Exome sequencing identifies SLC24A5 as a candidate gene for non-syndromic oculocutaneous albinism.J Invest Dermatol. 2013; 133: 1834-1840Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In addition, an OCA locus was mapped to 4q24 in a consanguineous Pakistani family, but the gene has not yet been described (Kausar et al., 2012Kausar T. Bhatti M.A. Ali M. et al.OCA5, a novel locus for non-syndromic oculocutaneous albinism, maps to chromosome 4q24.Clin Genet. 2012; 84: 91-93Crossref PubMed Scopus (70) Google Scholar). We analyzed 399 patients with non-syndromic OCA and found that 36% were OCA1, 25% had mutations in OCA2, 2% were OCA3, and 11% were caused by mutations in SLC45A2 (OCA4). An additional 6% of patients had mutations in GPR143 (OA1) and 1% in HPS1. Six percent of patients had a single heterozygous mutation in one gene, and in 13% no mutation in the known genes was identified (our unpublished data). Subsequently, we sequenced the nine exons of the SLC24A5 gene in 22 OCA patients without mutations in any of the known genes (OCA1–4, OA1, and HPS1 genes) and found 5 index patients with biallelic mutations (Table 1). No intragenic rearrangement (deletions, duplications) was identified.Table 1Phenotype and SLC24A5 mutations identified in patients with OCA6Patients060854070126131242070127100404110299120233Patient (Wei et al., 2013Wei A-H. Zang D-J. Zhang Z. et al.Exome sequencing identifies SLC24A5 as a candidate gene for non-syndromic oculocutaneous albinism.J Invest Dermatol. 2013; 133: 1834-1840Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar)Age at presentation (years)1620162314193SexMaleMaleMaleMaleFemaleMaleFemaleMaleClinicVannesToulouseToulouseToulouseAngersGhentBrusselsNDEthnic and geographic originFrenchPortuguesePortuguesePortugueseFrenchSyrianBelgianAsianParental consanguinityNoYesYesYesNoYesNoNoHair colorBlondLight brownLight brownLight brownPlatinum blondLight brownLight brownLight brownSkin colorFairFairFairFairFairFairFairFairTendancy to tanYesYesYesYesNoNoYesYesPigmented nevusNDYesYesYesNoNoYesNDReduced visual acuityYesYesYesYesYesYesYesYesBest-corrected visual acuityND0.30 RE/0.40 LE0.25 RE/0.40 LE0.40 RE/0.30 LE0.125 RE/0.125 LE0.15 RE/ 0.20 LE0.20 RE/0.30 LE0.20 RE/0.20 LENystagmusYesYesYesYesYesYesYesYesIris colorBlueGreenGreenGreenBlueBlueGreenBrownishIris transilluminationYesYesYesYesYesYesYesYesFoveal hypoplasiaYesYesYesYesYesYesYesYesRetinal hypopigmentationYesYesYesYesYesYesYesYesHearing lossYesNoNoNoNoNoNDNDAssociated findings (bleeding, granulomatous colitis, pulmonary involvement, recurrent infectious diseases)NoNoNoNoNoNoNoNoMutationsHmz mutationHmz mutationHmz mutationHmz mutationMutation 1Mutation 2Hmz mutationMutation1Mutation 2Mutation1Mutation 2c.590+4A>Gc.641delTc.641delTc.641delTc.344C>Ac.989G>Ac.546T>Ac.216T>Ac.344C>Ac.591G>Ac.1361insTAA nomenclaturep.?p.Leu214ArgfsX12p.Leu214ArgfsX12p.Leu214ArgfsX12p.Ala115Glup.Trp330Xp.Ser182Argp.Tyr72Xp.Ala115Glup.Trp197Xp.Cys46LeufxX43Variant typeSpliceTruncatingTruncatingTruncatingMissenseTruncatingMissenseTruncatingMissenseNonsenseTruncatingExon56662752259Polyphen————Probably damaging—Probably damaging/Probably damagingProbably damaging—Conservation————AA highly conserved—AA highly conserved/AA highly conservedAA highly conserved—Frequency (%), HapMap/1000 Genomes0/00/00/00/00/00/00/00/00/00/00/0Abbreviations: Hmz, homozygous; LE, left eye; ND, not determined; RE, right eye.p.? corresponds to the common nomenclature for mutations the effect of which is not known at the protein level. Open table in a new tab Abbreviations: Hmz, homozygous; LE, left eye; ND, not determined; RE, right eye. p.? corresponds to the common nomenclature for mutations the effect of which is not known at the protein level. Patients 060854, 070126, and 110299 were homozygous for mutations c.590+4A>G, c.641delT/p.Leu214ArgfsX12, and c.546T>A/p.Ser182Arg, respectively. The affected brother (131242) and first cousin (0710127) of patient 070126 were also homozygous for the c.641delT/p.Leu214ArgfsX12 mutation. His unaffected brother was heterozygous for the mutation. Compound heterozygosity was found in patients 100404 (c.344C>A/p.Ala115Glu and c.989G>A/p.Trp330X) and 120233 (c.216T>A/p.Tyr72X and a c.344C>A/p.Ala115Glu). All the identified mutations were inherited from heterozygous parents and were absent from single-nucleotide polymorphism databases (HapMap, 1000 Genomes). The two missense mutations c.546T>A/p.Ser182Arg and c.344C>A/p.Ala115Glu were predicted to be probably damaging by the prediction software Polyphen2. Moreover they affected highly conserved amino acids. We observed a heterogeneous phenotype among the seven OCA patients with SLC24A5 mutations reported herein (Table 1 and Figure 1). Severe hypopigmentation similar to that observed in OCA1 (white platinum golden hair and complete iris transillumination) was observed in patient 100404, whereas a milder skin phenotype with light brown hair was observed in four patients. Patient 110299 had light brown hair, but no skin pigmentation, revealing subcutaneous vascular structures. No ocular pigmentation was observed, with complete iris transillumination and absent pigmentation of the retinal pigment epithelium and choroid on fundoscopy. However, patient 120233, who had darker hair, displayed some degree of ocular pigmentation. The patient published by Wei et al., 2013Wei A-H. Zang D-J. Zhang Z. et al.Exome sequencing identifies SLC24A5 as a candidate gene for non-syndromic oculocutaneous albinism.J Invest Dermatol. 2013; 133: 1834-1840Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar also had blond/light brown hair. Obviously, solid genotype–phenotype correlations cannot yet be established because of the small number of OCA6 patients identified to date. Ophthalmologic anomalies were always present and included reduced best-corrected visual acuity, nystagmus, pronounced iris transillumination, severe retinal hypopigmentation, and foveal hypoplasia. No other findings evocative of syndromic OCA, including bleeding, granulomatous colitis, pulmonary involvement, or propensity to infections, were recorded. SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium–calcium exchange activity that regulates human epidermal melanogenesis (Ginger et al., 2008Ginger R.S. Askew S.E. Ogborne R.M. et al.SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis.J Biol Chem. 2008; 283: 5486-5495Crossref PubMed Scopus (116) Google Scholar). Slc24a5-null mice have been reported to have albinotic features (Vogel et al., 2008Vogel P. Read R.W. Vance R.B. et al.Ocular albinism and hypopigmentation defects in Slc24a5-/- mice.Vet Pathol. 2008; 45: 264-279Crossref PubMed Scopus (51) Google Scholar). Slc24a5 mutations are responsible for the golden mutant in the zebrafish, in which melanosomal changes have been identified. Slc24a5 was considered to be a putative cation exchanger (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor, in golden. The human ortholog of slc24a5 is highly conserved (68% at the mRNA level; 69% at the protein level) and was shown to be functional in the zebrafish (Lamason et al., 2005Lamason R.L. Mohideen M-APK. Mest J.R. et al.SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.Science. 2005; 310: 1782-1786Crossref PubMed Scopus (787) Google Scholar). A genome-wide association study performed in a South Asian population showed that SLC24A5 single-nucleotide polymorphism rs1426654 (Ala111Thr) was associated with lighter skin in Thr111-positive individuals, and might be a natural regulator of human skin color variation (Stokowski et al., 2007Stokowski R.P. Pant P.V.K. Dadd T. et al.A genomewide association study of skin pigmentation in a South Asian population.Am J Hum Genet. 2007; 81: 1119-1132Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Wei et al., 2013Wei A-H. Zang D-J. Zhang Z. et al.Exome sequencing identifies SLC24A5 as a candidate gene for non-syndromic oculocutaneous albinism.J Invest Dermatol. 2013; 133: 1834-1840Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar reported less mature and more immature melanosomes in epidermal melanocytes of their OCA6 patient, supporting the involvement of SLC24A5 in the maturation of melanosomes or in the production of pigment in mature melanosomes. It was shown that HPS protein–associated complexes such as AP-3, BLOC-1, and BLOC-2 mediated the transport of melanosomal proteins such as Tyrosinase, TYRP1, OCA2, and ATP7A into mature melanosomes (Wei and Li, 2013Wei A.H. Li W. Hermansky-Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis.Pigment Cell Melanoma Res. 2013; 26: 176-192Crossref PubMed Scopus (105) Google Scholar). It was also suggested that BLOC-1 and BLOC-2, involved in Hermanski–Pudlak syndrome, could mediate the melanosomal targeting of SLC24A5, but this requires further investigations. Our finding of mutations in SLC24A5 in five unrelated families strengthens the importance of screening this gene in OCA, and indicates that OCA6 is not restricted to the Chinese population and accounts for 1.25% of OCA patients in our series. Still, 11.5% of patients have no mutation after extensive analysis of the OCA1–4, OCA6, OA1, and HPS1 genes, thus suggesting that other genes involved in OCA still remain to be identified. Written informed consent was received from the patients. The authors adhere to the Declaration of Helsinki Principles. Experiments were approved by the Comité de protection des Personnes Bordeaux—Outre Mer III. We wish to thank the French Albinism Association Genespoir, the Union Nationale des Aveugles et Déficients Visuels, and the Ministry of Health (France) for their financial support. FM-P had a PhD studentship from the Fondation pour la Recherche Médicale (France). DNA sequencing was performed at the Genome Transcriptome Platform of Bordeaux (grants from the Conseil Régional d'Aquitaine nos 20030304002FA and 20040305003FA and from the European Union, FEDER no. 2003227). BPL is a senior clinical investigator of the Research Foundation Flanders (FWO).