Impact of a SLC24A5 variant on the retinal pigment epithelium of a Japanese patient with oculocutaneous albinism type 6

Abstract

Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+‐dependent Na+/Ca2+ exchanger 5. NCKX5 is involved in the maturation of melanosomes, but its function is still unclear. In this study, we characterized a Japanese patient with OCA6. Genetic analysis revealed compound heterozygous variants in SLC24A5, c.590 + 1dupG, and c.598G>A (p.G200R). To clarify the functional significance of the missense variant, we generated a knock‐in (KI) mouse model carrying the mouse homolog of the G200R variant using the CRISPR/Cas9 system. Chemical analysis showed decreased amounts of eumelanin in the hair and skin of KI mice, while levels of benzothiazine units in pheomelanin were significantly increased in their hair. Retinal pigment was also decreased in KI mice. Notably, a histopathologic study revealed a significant pigment loss in the retinal pigment epithelium (RPE) but not in the choroid. Immunohistochemically, the expression of NCKX5 in the RPE was decreased but was maintained in the choroid of KI mice. These findings could explain the difference in phenotypic severity between eye symptoms and hypopigmentation in the skin/hair.

Genetic insights into Tietz albinism‐deafness syndrome: A new dominant‐negative mutation in MITF

“…PM has been demonstrated to contribute to carcinogenesis through both UV‐dependent and UV‐independent pathways through the production of reactive oxygen species (Mitra et al., 2012). We previously reported that patients with oculocutaneous albinism (OCA) and Hermansky‐Pudlak syndrome (HPS) exhibit significantly elevated levels of 4‐AHP, a marker of BT‐PM that is potentially associated with a high risk of skin cancer (Okamura et al., 2018; Saito et al., 2022). In this case, there was a substantial reduction in both EM and PM, thus raising concerns regarding UV‐induced carcinogenesis.…”

Identification and expression of the target gene SLC24A2 of oar-miR-377 and its novel SNPs effects on wool traits in sheep

“…Although there is no direct evidence that SLC24A2 is related to skin hair follicles, SLC24A5 has been con rmed to be related to animal hair color (Jorgenson et al 2020). RT-PCR results showed that the SLC24A5 gene was highly expressed in skin and eyes and low expressed in other tissues, while the expression level in mouse melanoma was more than 100 times higher than that in normal skin and eyes (Childebayeva et al 2022;Saito et al 2022). Our previous research showed that SLC24A2 is a key molecule in hair follicle development signal transduction which also is the target gene of the oar-miR-377 by microRNA-sequencing analysis.…”

Skin colour: A window into human phenotypic evolution and environmental adaptation

“…SLC24A5 also regulates melanin changes in other vertebrate species, such as mice and zebrafish. In addition, mutations in SLC24A5 can cause non-syndromic oculocutaneous albinism (Ju & Mathieson, 2021;Lin et al, 2018;Saito et al, 2022;Wei et al, 2013). In the mouse, the most common model animal, Slc24a5 protein plays an important role in the neuroepithelial pigment cells of the mouse eye.…”