Oculocutaneous albinism type 4 (OCA4) is traditionally classified as an autosomal recessive disorder. Although the human Y70H variant has recently been suggested to exert a dominant-negative effect, it remains unknown whether this represents an isolated rarity or a manifestation of a broader pathogenic principle. Here, we identified a common dominant-negative SLC45A2 mutation spectrum based on its intracellular localization. Using a zebrafish model to systematically screen ten clinical variants, we identified four specific mutations, Y70H, D157 N, G188V, and L374F, which exerted potent dominant-negative effects in vivo. Subcellular localization analysis in B16 melanoma cells revealed that these mutant proteins exhibited significantly higher endoplasmic reticulum (ER) occupancy than the wild-type (WT) protein. Importantly, these variants act as "molecular traps" by physically sequestering WT SLC45A2 within the ER, thereby drastically reducing its delivery to TYRP1-positive melanosomes. Our findings demonstrate that dominant inheritance in OCA4 is driven by the spatial sequestration of functional proteins within the ER quality control machinery. This study establishes a new conceptual framework for the molecular diagnosis of OCA4 and provides a functional rationale for the use of pharmacological chaperones to rescue trapped transporters in membrane protein disorders. Oculocutaneous albinism type 4 (OCA4) is characterized by: (1) the ocular changes found in all types of albinism that include nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity that depends on the amount of iris and retinal pigment; and misrouting of the optic nerves at the chiasm associated with alternating strabismus, reduced stereoscopic vision, and altered visual evoked potential; and (2) reduced pigmentation of the skin and hair that ranges from minimal to near normal. Infants with OCA4 are usually recognized by age one year due to hypopigmentation of the skin and hair that ranges in color from silvery white to light yellow. Although hair color may darken with time, it does not vary significantly from childhood to adulthood. The diagnosis of OCA4 is established in a proband with suggestive findings and biallelic pathogenic variants in SLC45A2 identified by molecular genetic testing. Treatment of manifestations: Correction of refractive errors with spectacles or contact lenses to improve visual acuity. Strabismus surgery may be considered for cosmetic reasons. Although dark glasses may reduce photophobia, they may also reduce vision; thus, a hat with a brim or visor is best to reduce photophobia. Protection from the sun by wearing protective clothing and regular application of topical sunscreens is essential to prevent sunburn and secondary skin changes, and to decrease the risk of skin cancer later in life. Individuals with OCA4 should stay out of the sun from an early age, because cumulative ultraviolet exposure is a major risk factor for skin cancers. Surveillance: Annual ophthalmologic examination and reassessment for accurate correction of refractive error. Evaluation of the skin for cancer screening every six months is recommended. Agents/circumstances to avoid: Prolonged exposure of the skin to the sun, activities without appropriate eye protection from the sun, and tanning beds and artificial ultraviolet sources. OCA4 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC45A2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC45A2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Oculocutaneous albinism (OCA) is a complex genetic disorder characterized by reduced or absent pigmentation in the skin, hair, and eyes. Among the eight known subtypes, OCA-4 is caused by a mutation in SLC45A2, which plays a crucial role in melanin biosynthesis. While autosomal recessive inheritance is the most common pattern for all OCA subtypes, autosomal dominant cases are extremely rare. We report three patients from a Chinese family exhibiting autosomal dominant OCA-4. Clinical assessments evaluated pigmentation and ocular features in affected family members. Next-generation sequencing was performed to identify pathogenic variants, and functional studies in MNT-1 cells were performed to explore the variant's biological effects. Patients exhibited mild hypopigmentation and foveal hypoplasia, consistent with the OCA-4 phenotype. Genetic analysis identified a heterozygous c.208T>C (p.Tyr70His) variant in SLC45A2, the same variant that has been previously reported in association with autosomal dominant OCA-4. Functional studies demonstrated that this variant caused protein retention in the endoplasmic reticulum, resulting in reduced melanin production. This family represents the first documented cases of autosomal dominant OCA-4 in the Chinese population and only the second reported worldwide. Our findings confirm that the p.Tyr70His variant causes autosomal dominant OCA-4. This study deepens our understanding of OCA-4's genetic mechanisms and increases the complexity of its inheritance patterns in genetic counseling.

Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants. To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation. Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations. Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed. We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.