Structure of the SLC7A7 gene and mutational analysis of patients affected by lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of cationic amino acid transport caused by mutations in the SLC7A7 gene. We report the genomic structure of the gene and the results of the mutational analysis in Italian, Tunisian, and Japanese patients. The SLC7A7 gene consists of 10 exons; sequences of all of the exon-intron boundaries are reported here. All of the mutant alleles were characterized and eight novel mutations were detected, including two missense mutations, 242A-->C (M1L) and 1399C-->A (S386R); a nonsense mutation 967G-->A (W242X); two splice mutations IVS3 +1G-->A and IVS6 +1G-->T; a single-base insertion, 786insT; and two 4-bp deletions, 455delCTCT and 1425delTTCT. In addition, a previously reported mutation, 1625insATCA, was found in one patient. It is noteworthy that 242A-->C causes the change of Met1 to Leu, a rare mutational event previously found in a few inherited conditions. We failed to establish a genotype/phenotype correlation. In fact, both intrafamilial and interfamilial phenotypic variability were observed in homozygotes for the same mutation. The DNA-based tests are now easily accessible for molecular diagnosis, genetic counseling, and prenatal diagnosis of LPI.

Early detection of lung involvement in lysinuric protein intolerance: role of high-resolution computed tomography and radioisotopic methods.

Pulmonary disease of unknown etiology is a potentially fatal complication in patients with lysinuric protein intolerance (LPI), an autosomal recessive disorder caused by the defective transport of cationic amino acids. Lung involvement was investigated in nine Italian LPI patients through pulmonary function tests and lung imaging studies consisting of conventional chest radiography, high-resolution computed tomography (HRCT), and perfusion and ventilation scintigraphy. One 10-yr-old patient died of severe respiratory insufficiency from alveolar proteinosis. All of the remaining patients were asymptomatic at the time of the study, although HRCT scans revealed signs of lung involvement defined by the presence of acinar nodules, inter- and/or intralobular thickening of the interstitial septa, and subpleural cysts in five of the patients. Radioisotope studies showed an uneven distribution of perfusion and ventilation, and confirmed the presence of segmental and/or diffuse pulmonary functional defects. No abnormalities of pulmonary function were evident, and answers to a questionnaire excluded primary coexisting lung disease. In patients with LPI, including those without clinical and functional impairment, HRCT and radioisotopic studies appear to be the most sensitive methods for the early diagnosis of lung disease and correct assessment of its progression.