Whole exome sequencing identifies a novel pathogenic variation [p.(Gly194valfs*7)] in SLC45A2 in the homozygous state in multiple members of a family with oculocutaneous albinism in southern India

Abstract

Deleterious mutations within the SLC45A2 gene, encoding membrane-associated transporter protein (MATP), are responsible for type 4 oculocutaneous albinism. The cytogenetic location of SLC45A2 is 5p13.2 and it comprises seven exons located over around 40 kb. Its encoded protein, MATP, is 530 amino acids long and has 12 putative transmembrane domains. MATP is synthesized within melanocytes. It is in these cells that melanogenesis takes place and the melanin is contained within specialized organelles called melanosomes. Previous studies have shown that when MATP expression was reduced using small interfering RNA in MNT-1 melanoma cells, pH was lowered within melanosomes, they became poorly melanized and tyrosinase activity within melanocytes was also reduced. This type of albinism produces a broad spectrum of phenotypes, ranging from complete absence of melanin to brown hair and brown irides. In the current study, blood was collected from a family in which four members had oculocutaneous albinism, showing a complete absence of melanin in skin, hair and eyes. Screening of the TYR gene using the extracted DNA showed no mutation and therefore whole exome sequencing analysis was performed. A novel deletion mutation c.579delG [p.(Gly194Valfs*7)] in the SLC45A2 gene, predicted to be pathogenic and to result in both frameshift and premature termination of the MATP chain, was identified. These data add to the information pertaining to the mutation spectrum of OCA4.Oculocutaneous albinism (OCA) is a congenital disorder characterized by a reduction or complete absence of melanin pigments in the skin, hair and eyes. Pigment deficiencies of the skin make development of naevi and ephelids more likely and increase susceptibility to skin cancer. Visual acuity is diminished to varying degrees in most people with OCA, and is caused by refractive errors, colour vision impairment, reduced stereoscopic vision, strabismus, nystagmus and macular (foveal) hypoplasia. Inheritance of OCA is mostly autosomal recessive and caused by pathogenic mutations in multiple genes that encode proteins involved in melanin biosynthesis. 1 Type 1 OCA, associated with mutations in the tyrosinase gene (TYR), is the most common type of this disorder in India. The less common type 4 OCA (MIM 606574), estimated to comprise approximately 10% of all OCA cases in India, is caused by mutations in the solute carrier family 45 member 2 (SLC45A2) gene, also called the membraneassociated transporter protein (MATP) gene. 2,3 Approximately 90 pathogenic variants of SLC45A2 have been reported to date. The phenotypes associated with OCA4 vary from a complete absence of melanin to development of brown hair and brown irides. 4 Individuals with OCA4 most often have compound heterozygous SLC45A2 pathogenic mutations rather than having just one pathogenic variant in the 409 ª 2019 British Association of Dermatologists homozygous state. 3,4 Although the function of MATP within melanocytes is still not completely understood, a study using small interfering RNA against SLC45A2 mR...

Evident hypopigmentation without other ocular deficits in Dutch patients with oculocutaneous albinism type 4

“…While most reports describe pigmentation levels of skin and hair, ophthalmic details are usually scarce. Some studies report absence of nystagmus in some patients 9 , 10 , 13 , 15 , 17 – 20 . Visual acuities in OCA4 patients in earlier reports ranged from − 0.1 to 1.5 logMAR, with most patients having poor VA 6 , 9 , 14 , 16 , 18 , 25 , 26 , 28 , 41 .…”