Albinism is a pigmentation disorder characterized by visual impairment, isolated (Ocular Albinism, OA) or associated with generalized skin and hair hypopigmentation (Oculo-Cutaneous Albinism, OCA), and sometimes with other ...
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Albinism is a pigmentation disorder characterized by visual impairment, isolated (Ocular Albinism, OA) or associated with generalized skin and hair hypopigmentation (Oculo-Cutaneous Albinism, OCA), and sometimes with other symptoms in syndromic forms called Hermansky-Pudlak (HPS) and Chediak-Higashi (CHS) syndromes. Most are autosomal recessive affections except for X-linked OA. Prior to this work 19 genes were known to cause isolated or syndromic albinism. After extensive analysis of these genes, 25 to 30% of patients remain molecularly unsolved. To search for new genes we screened, in 230 patients without molecular diagnosis, a panel of 129 candidate genes. We identified deleterious variants in two candidate genes. First, we report two patients with predicted loss-of-function variants in BLOC1S5 in two patients. The first patient carries an intragenic homozygous deletion involving exons 3 and 4. The second patient has a homozygous one base-pair deletion in exon 4. BLOC1S5 codes for one of the 8 subunits of BLOC-1, three of which are involved HPS-7, 8 and 9. Both patients had mild hypopigmentation, classical ocular albinism and moderate bleeding diathesis, platelet aggregation deficit and a very low number of platelet dense granules, compatible with HPS. Patient 1’s platelets displayed an absence of BLOC-1, showing that the identified mutation disrupts BLOC1S5 function and impairs BLOC-1 assembly. Whereas expression of a wild-type BLOC1S5 protein in non-pigmented murine melanocytes rescued pigmentation, assembly of a functional BLOC-1, and melanosome cargo trafficking, expression of the patient's BLOC1S5 variant allele did not. These data indicate that mutation of BLOC1S5 is disease-causing, and we propose that BLOC1S5 is the gene for a new form of HPS, HPS11. The second gene, DCT or TYRP2 has been suspected for a long time, due to its collaboration with TYR (OCA1) and TYRP1 (OCA3). We describe two unrelated patients presenting with clinical diagnosis of OCA. One patient is homozygous for a missense variant in the exon 1 of DCT and the other is a compound heterozygote for a missense variant in exon 1 and a frame-shift deletion in exon 9. Both missense variants, affecting highly conserved cysteine, were introduced in mice via Crispr-Cas9, which led to mild hypopigmentation of the fur and ocular anomalies. A Zebrafish knock-down model has also been produced by morpholino injection, leading to a significant decrease in melanin levels compared to controls. We propose that DCT is the gene for a new form of OCA, OCA8. In this work we also describe three unrelated patients with novel variants in BLOC1S3 responsible for HPS-8. This rare form of HPS had been reported in only two families and we believe detailed clinical description of patients is useful for clinicians for patient’s diagnosis and prognosis evaluation and genetic counseling. In conclusion we have reported two new genes involved in isolated and syndromic forms of albinism as well as new insight in an already known yet rare form of syndromic albinism.
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