Two novel splicing mutations in the SLC45A2 gene cause Oculocutaneous Albinism Type IV by unmasking cryptic splice sites

Abstract

Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. OCA type IV (OCA4) is one of the four commonly recognized forms of albinism, and is determined by mutation in the SLC45A2 gene. Here, we investigated the genetic basis of OCA4 in an Italian child. The mutational screening of the SLC45A2 gene identified two novel potentially pathogenic splicing mutations: a synonymous transition (c.888G>A) involving the last nucleotide of exon 3 and a single-nucleotide insertion (c.1156+2dupT) within the consensus sequence of the donor splice site of intron 5. As computer-assisted analysis for mutant splice-site prediction was not conclusive, we investigated the effects on pre-mRNA splicing of these two variants by using an in vitro minigene approach. Production of mutant transcripts in HeLa cells demonstrated that both mutations cause the almost complete abolishment of the physiologic donor splice site, with the concomitant unmasking of cryptic donor splice sites. To our knowledge, this work represents the first in-depth molecular characterization of splicing defects in a OCA4 patient.

Bird Integumentary Melanins: Biosynthesis, Forms, Function and Evolution

“…On the other hand, Slc45a2, also known as MATP (membrane-associated transporter protein) in mammals, has an important role in vesicle sorting in melanocytes and in trafficking melanogenic enzymes. Its mutation causes OCA4 in humans [ 100 ] and melanin-based plumage color variation in chicken and Japanese quail. The mechanism of melanin regulation and the pattern of Scl45a2 mutations in birds is complex and poorly understood, as some mutations cause complete absence of pigmentation while other cause a specific inhibition of pheomelanogenesis [ 101 ].…”

Skin Pigmentation Genetics for the Clinic

“…Mutation of SLC45 A2 leads to OCA4 [68] . It is known that MATP abrogation leads to lowered melanosomal pH, and reduced tyrosinase activity, possibly due to its effects on copper binding to tyrosinase protein.…”

An Unusual Phenotype in Dutch Patients With Oculocutaneous Albinism Type 4: Evident Hypopigmentation Without Other Ocular Deficits.

“…In contrast to the homogeneous hypopigmentation phenotype we found in our cohort, in the literature the degree of pigmentation seems to vary from complete lack of pigmentation to very mild hypopigmentation. 1,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 While most reports describe pigmentation levels of skin and hair, ophthalmic details are usually scarce. Some studies report absence of nystagmus in some patients.…”

“…4 Since then, many patients have been described with variable phenotypes, from complete absence of pigmentation to subtle hypopigmentation only. 1,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 World prevalence of OCA4 is estimated around 1:100.000, which is 3-19% of all OCA cases. 5,17,30,7,14,15,24,25,31,32 In Japan OCA4 is more common, with a frequency of 27% of all OCA cases.…”