title: 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.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italia.
authors.forename: Letizia
authors.initials: L
authors.lastname: Straniero
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano (Mi), Italy.|Humanitas Clinical and Research Center, Rozzano (Mi), Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Rimoldi
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano (Mi), Italy.|Humanitas Clinical and Research Center, Rozzano (Mi), Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
authors.affiliation: Medical Genetics Unit-Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mauri
authors.affiliation: Medical Genetics Unit-Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Manfredini
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Andreucci
authors.affiliation: Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bargiacchi
authors.affiliation: Medical Genetics Unit-Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
authors.affiliation: Medical Genetics Unit-Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Giovanni P
authors.initials: GP
authors.lastname: Gesu
authors.affiliation: Pediatric Ophthalmology Department, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Del Longo
authors.affiliation: Pediatric Ophthalmology Department, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piozzi
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano (Mi), Italy.|Humanitas Clinical and Research Center, Rozzano (Mi), Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Medical Genetics Unit-Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Primignani
mesh_terms: D016115:Albinism, Oculocutaneous / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D002675:Child, Preschool; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D026901:Membrane Transport Proteins; D022821:RNA Splice Sites; C510061:SLC45A2 protein, human