title: Lysinuric protein intolerance: identification and functional analysis of mutations of the SLC7A7 gene.
abstract: Lysinuric protein intolerance (LPI) is an inherited hyperdibasic aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is relatively common in Finland and a few clusters of patients are known in Italy and Japan. The SLC7A7 gene, mutated in LPI patients, encodes the y+LAT-1 protein which is the light subunit of a heterodimeric CAA transporter. We performed the mutation analysis in seven probands from five unrelated LPI families and identified five novel SLC7A7 mutations (p.M50K, p.T188I, p.R333M, p.Y457X, and c.499+?_629-?). By expression studies in X. laevis oocytes or patient's renal tubular cells, the functional analysis of altogether eight SLC7A7 mutations is here reported. Noteworthy, the p.R333M mutation, caused by a G to T transversion of the last nucleotide at 3' end of exon 7, disrupts a functional splicing motif generating misspliced transcripts. Three of the novel mutations were found in patients originating from Greece and Pakistan thus increasing the list of ethnic backgrounds where LPI mutant alleles are present. This reinforces the view that the rarity of LPI outside Finland might be ascribed to misdiagnosis of this disease.
authors.affiliation: Department of Pediatrics, Federico II University, Naples, Italy. mpsperandeo@dti.telethon.it
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sperandeo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Annunziata
authors.forename: Virginia
authors.initials: V
authors.lastname: Ammendola
authors.forename: Valentina
authors.initials: V
authors.lastname: Fiorito
authors.forename: Antonio
authors.initials: A
authors.lastname: Pepe
authors.forename: Maria Virginia
authors.initials: MV
authors.lastname: Soldovieri
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sebastio
mesh_terms: D000483:Alleles; D020157:Amino Acid Transport Disorders, Inborn / Q000235:genetics* / Q000473:pathology; D027241:Amino Acid Transport System y+L; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004252:DNA Mutational Analysis; D019281:Dimerization; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D005091:Exons; D005260:Female; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics*; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism; D008239:Lysine / Q000737:chemistry*; D008297:Male; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014982:Xenopus laevis
chemical_list: D027241:Amino Acid Transport System y+L; D027301:Fusion Regulatory Protein 1, Light Chains; C421261:SLC7A7 protein, human; D008239:Lysine