Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1.
Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1.
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婴儿高钙血症1型（HCINF1），以前被称为特发性婴儿高钙血症，是由25-羟基维生素D 24-羟化酶基因CYP24A1突变引起的。CYP24A1中的R396W功能缺失突变是HCINF1感染患者中观察到的第二常见突变等位基因。我们在敲入小鼠的小鼠Cyp24a1基因中引入了位点特异性R396W突变，以产生HCINF1的人源化模型。在C57Bl6自交系背景下，纯合突变小鼠表现出较高的围产期死亡率，断奶后存活率为17%。这是通过对CD1近交背景的杂交来纠正的。突变动物在出生后第一周出现高钙血症，发展为肾结石，并且具有非常高的25(OH)D3与24,25(OH)2D3比率，这是HCINF1病症的诊断标志。突变体Cyp24a1等位基因的表达高度升高，而Cyp27b1的表达则被消除。在CD1-R396w/w突变动物中检测到骨折愈合受损。C57Bl6-R396W毒株的致死性增强表明其受不同遗传背景的影响。我们的数据指向了独特敲入小鼠的效用，以探索与其他生物和环境因素隔离的CYP24A1变异的生理影响。
Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine Cyp24a1 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)D3 to 24,25(OH)2D3 ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant Cyp24a1 allele was highly elevated while Cyp27b1 expression was abrogated. Impaired bone fracture healing was detected in CD1-R396w/w 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.