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 (Slc7a7^{em1Lbu/em1Lbu}; Slc7a7^Lbu/Lbu and Slc7a7^{em1(IMPC)Bay/em1(IMPC)Bay}; Slc7a7^Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7^Lbu/Lbu and Slc7a7^Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7^Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7^Lbu/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 Slc7a7^Lbu/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 Slc7a7^Lbu/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 Slc7a7^Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

中文翻译：

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全球 Slc7a7 敲除小鼠模型展示了人类赖氨酸尿蛋白不耐受的特征表型。


赖氨酸尿蛋白不耐受 (LPI) 是由SLC7A7中的双等位基因致病变异引起的阳离子氨基酸（精氨酸、赖氨酸、鸟氨酸）运输的先天性错误，SLC7A7 编码 y ⁺ LAT1 转运蛋白的轻亚基。 LPI 并发症（包括生长障碍、肾脏疾病、肺泡蛋白沉积症、自身免疫性疾病和骨质疏松症）的治疗方法有限。鉴于唯一已发表的全球SLC7a7敲除小鼠模型的早期致死率，需要一种可行的动物模型来研究全球SLC7A7缺陷。因此，我们使用 CRISPR/Cas9 技术，通过引入缺失，生成了两种具有全局Slc7a7缺陷的小鼠模型 ( Slc7a7 ^{em1Lbu/em1Lbu} ; Slc7a7 ^Lbu/Lbu和Slc7a7 ^{em1(IMPC)Bay/em1(IMPC)Bay} ; Slc7a7 ^Bay/Bay )外显子 3 和 4。分别在 C57BL/6 和 C57BL/6NJ 近交遗传背景的Slc7a7 ^Lbu/Lbu和Slc7a7 ^Bay/Bay小鼠中观察到围产期致死率。我们注意到Slc7a7 ^Lbu/Lbu小鼠在 129 Sv/Ev × C57BL/6 F2 背景下的存活率有所提高，但发生了出生后生长障碍。与人类 LPI 一致，这些Slc7a7 ^Lbu/Lbu小鼠表现出血浆中阳离子氨基酸浓度降低和尿液浓度升高。组织病理学评估显示Slc7a7 ^Lbu/Lbu小鼠肾皮质刷状缘丧失和脂质空泡形成，结合氨基酸尿提示近端肾小管功能障碍。 L ₄椎骨的微型计算机断层扫描和骨骼射线照片分别显示Slc7a7 ^Lbu/Lbu小鼠骨骼发育延迟并表明矿化减少。除了骨骼发育迟缓和肾脏发育迟缓外，还根据组织病理学评估观察肺和肝脏的发育迟缓。总体而言，我们的 F2 混合背景上的Slc7a7 ^Lbu/Lbu小鼠模型概括了多种人类 LPI 表型，可能对未来 LPI 病理学研究有用。