@article{12df4ec45e904c24b40e7e5edc6b832f,
title = "A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance",
abstract = "Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.",
author = "Stroup, {Bridget M.} and Ronit Marom and Xiaohui Li and Hsu, {Chih Wei} and Chang, {Cheng Yen} and Truong, {Luan D.} and Brian Dawson and Ingo Grafe and Yuqing Chen and Jiang, {Ming Ming} and Denise Lanza and Green, {Jennie Rose} and Qin Sun and Barrish, {J. P.} and Safa Ani and Christiansen, {Audrey E.} and Seavitt, {John R.} and Dickinson, {Mary E.} and Farrah Kheradmand and Heaney, {Jason D.} and Brendan Lee and Burrage, {Lindsay C.}",
note = "Funding Information: National Institutes of Health (5T32DK007664-28 to B.M.S.); U.S. Public Health Service (grant P30DK56338 to B.M.S.), which funds the Texas Medical Center for Digestive Disease Center; National Institutes of Health (T32GM007526-11 to R.M.); Rolanette and Berdon Lawrence Award of the Bone Disease Program of Texas (to R.M.); BCM Comprehensive Cancer Training Program (CPRIT RP160283 to C.Y.C.); National Institutes of Health (R03DE026233 to I.G.); National Institutes of Health (DK102641, AR071741 to B.L.); National Institutes of Health (K08DK106453 to L.C.B.); Caroline Wiess Law Fund for Research in Molecular Medicine at Baylor College of Medicine and Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (HD024064) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development; Dan L. Duncan Comprehensive Cancer Center P30 (CA125123 to BCM Pathology and Histology Core, Mouse Embryonic Stem Cell Core, and Gastrointestinal Experimental Model Systems (GEMS) Core). National Institutes of Health (UM1 HG006348 to BCM Knockout Mouse Production and Phenotyping Program (KOMP2)). The BCM Integrated Microscopy Core is supported by National Institutes of Health (DK56338, CA125123), CPRIT (RP150578, RP170719), the Dan L. Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. Publisher Copyright: {\textcopyright} The Author(s) 2020. Published by Oxford University Press. All rights reserved",
year = "2020",
month = jul,
day = "1",
doi = "10.1093/hmg/ddaa107",
language = "English (US)",
volume = "29",
pages = "2171--2184",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "13",
}