Publication Date
8-1-2023
Journal
Disease Models & Mechanisms
DOI
10.1242/dmm.050118
PMID
37486182
PMCID
PMC10445726
PubMedCentral® Posted Date
8-17-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Amino Acid Transport System y+L, Mice, Inbred C57BL, Mice, Knockout, Disease Models, Animal, Amino Acid Metabolism, Inborn Errors, Hearing Loss, Sensorineural, Mice, Animals, Growth Disorders, Insulin-Like Growth Factor I, Osteoporosis, Osteoblast, IGF-1, Lysinuric protein intolerance, Slc7a7, Arginine
Abstract
SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, but no differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell-autonomous and non-cell-autonomous mechanisms underlying phenotypes in LPI.
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