Research Centre, Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada.
Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0C7, Canada.
Nutrients. 2022 Aug 6;14(15):3221. doi: 10.3390/nu14153221.
Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, . The R396W loss-of-function mutation in is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine gene in knock-in mice to generate a humanized model of HCINF1. On the C57Bl6 inbred background, homozygous mutant mice exhibited high perinatal lethality with 17% survival past weaning. This was corrected by crossbreeding to the CD1 outbred background. Mutant animals had hypercalcemia in the first week of life, developed nephrolithiasis, and had a very high 25(OH)D to 24,25(OH)D ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant allele was highly elevated while expression was abrogated. Impaired bone fracture healing was detected in CD1-R396 mutant animals. The augmented lethality of the C57Bl6-R396W strain suggests an influence of distinct genetic backgrounds. Our data point to the utility of unique knock-in mice to probe the physiological ramifications of CYP24A1 variants in isolation from other biological and environmental factors.
婴儿高钙血症 1 型（HCINF1），以前称为特发性婴儿高钙血症，是由 25-羟维生素 D 24-羟化酶基因的突变引起的，。是在受影响的 HCINF1 患者中观察到的第二个最常见的突变等位基因。我们在敲入小鼠中引入了位于 基因中的特定位置 R396W 突变，以产生 HCINF1 的人源化模型。在 C57Bl6 近交系背景下，纯合突变小鼠在断奶后具有 17%的高围产期致死率。通过与 CD1 远交系杂交得到纠正。突变动物在生命的第一周出现高钙血症，发展为肾结石，并具有非常高的 25（OH）D 与 24、25（OH）D 的比值，这是 HCINF1 病症的诊断标志。突变 等位基因的表达高度升高，而 表达被阻断。在 CD1-R396 突变动物中检测到骨骨折愈合受损。C57Bl6-R396W 品系的致死率增加表明存在不同遗传背景的影响。我们的数据表明，独特的敲入小鼠可用于在没有其他生物学和环境因素的情况下单独探究 CYP24A1 变体的生理后果。
