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J Hum Genet. 2015 Sep;60(9):467-71. doi: 10.1038/jhg.2015.56. Epub 2015 May 28.

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

Author information

1
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italia.
2
Department of Biomedical Sciences, Humanitas University, Rozzano (Mi), Italy.
3
Humanitas Clinical and Research Center, Rozzano (Mi), Italy.
4
Medical Genetics Unit-Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
5
Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
6
Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.
7
Pediatric Ophthalmology Department, Niguarda Ca' Granda Hospital, Milan, Italy.

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.

PMID:
26016411
DOI:
10.1038/jhg.2015.56
[Indexed for MEDLINE]

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