A 4‐bp deletion promoter variant (rs984225803) is associated with mild OCA4 among Japanese patients

Abstract

Oculocutaneous albinism (OCA) type 4 is one of the most common types of albinism among Japanese population. In some patients who were clinically diagnosed with OCA, we have found a heterozygous pathological mutation in the coding region of SLC45A2, the gene responsible for OCA4, not leading to a DNA-based diagnosis. In this study, we evaluated pathological variants in the promoter region of SLC45A2 in these patients. The results indicated that the majority of the patients had a 4-bp deletion in the said region (c.-492_489delAATG; GenBank accession number: NM_016180; rs984225803) in the contralateral allele. These patients displayed a mild phenotype, especially regarding eye manifestations. The results of the luciferase reporter assay and electrophoretic mobility shift assay supported the pathological role of the variant. In addition, four of 220 alleles in Japanese normal control subjects also showed the deletion variant, indicating that this variant could possibly be a skin color-associated variant.

NGS‐based targeted resequencing identified rare subtypes of albinism: Providing accurate molecular diagnosis for Japanese patients with albinism

“…All of them demonstrated considerable pigmentation of the hair, irides, and skin, nystagmus, and photophobia. Patients with mild forms of non‐syndromic OCA such as OCA2 or OCA4, whose skin and/or hair tone resembles that of patients with BLOC‐2 mutations, often lack these ocular manifestations (Okamura et al, , ). However, patients with BLOC‐2 mutations are characterized by ocular defects such as nystagmus, which can already be detected during early infancy.…”

Homozygous promoter variant of SLC45A2 causes diverse hair color and patterns

“…1,2 Recently, a 4-bp deletion of the promoter region of SLC45A2, c.-492_489delAATG (rs984225803), was found to be a pathogenic variation that causes mild symptoms. 3 Until now, only two unrelated cases of children with a homozygote for the deletion have been reported and they showed an OCA-like phenotype. 4 Here, we report three siblings with the homozygous 4-bp deletion, which revealed diverse hair color and patterns.…”

“…It has been suggested that the 4-bp deletion decreases the transcription of skin-specific mRNA of SLC45A2. 3 A compound heterozygote of the 4-bp deletion and a null allele cause mild skin/hair symptoms and mild or no ophthalmologic abnormalities, while combinations of two null alleles cause severe phenotypes. There have been only two reported cases concerning the homozygous 4-bp deletion: 20-and 6-month-old unrelated patients, one of whom had blond hair with blackish streaks and the other had diffuse brown hair.…”

Current landscape of Oculocutaneous Albinism in Japan

“…Interestingly, the ranking in frequency of those two subtypes was opposite from a previous report [OCA1; 33.6%, OCA4; 27.2% from (Suzuki & Tomita, 2008)]. That discrepancy can be explained by the discovery of a 4‐bp deletion variant (c.‐492_489delAATG; GenBank accession number: NM_016180; rs984225803) in the promoter region of SLC45A2 , as an OCA‐causing variant (Okamura, et al., 2019). In this review, we define patients with compound heterozygous variations of a known pathological mutation in SLC45A2 and the 4‐bp deletion variant as a mild form of OCA4.…”