Abstract：
Vitamin D dependent rickets (VDDR) is a group of genetic disorders characterized by early-onset rickets due to deficiency of active vitamin D or a failure to respond to activated vitamin D. VDDR is divided into several subtypes according to the corresponding causative genes. Here we described a new type of autosomal dominant VDDR in a Chinese pedigree. The proband and his mother had severe bone malformations, dentin abnormalities, and lower serum 25 hydroxyvitamin D3 (25 (OH)D3) and phosphate levels. The proband slightly responded to high dose of vitamin D3 instead of daily low dose of vitamin D3. Whole exome sequencing, bioinformatic analysis, PCR and Sanger sequencing identified a nonsense mutation in CYP4A22 (c.900delG). The overexpressed wild type CYP4A22 mainly localized in endoplasmic reticulum and Golgi apparatus, and synthesized 25 (OH)D3 in HepG2 cells. The overexpressed CYP4A22 mutant increased the expression of CYP2R1 and produced little 25 (OH)D3 with vitamin D3 supplementation, which was reduced by CYP2R1 siRNA treatment. We concluded that CYP4A22 functions as a new kind of 25-hydroxylases for vitamin D3. Loss-of-function mutations in CYP4A22 lead to a new type of VDDR type 1 (VDDR1C). CYP2R1 and CYP4A22 may have some genetic compensation responding to nonsense-mediated mRNA decay effect of each other.
A nonsense mutation in CYP4A22 was found in a Chinese pedigree with vitamin D dependent rickets and low serum phosphate. CYP4A22 localizes in endoplasmic reticulum and Golgi apparatus, and processes 25-hydroxylase activity in liver cells. CYP4A22 loss of function reduce the synthesis of 25(OH)D3 and cause genetic compensation of CYP2R1.
A nonsense mutation in CYP4A22 was found in a Chinese pedigree with vitamin D dependent rickets and low serum phosphate. CYP4A22 localizes in endoplasmic reticulum and Golgi apparatus, and processes 25-hydroxylase activity in liver cells. CYP4A22 loss of function reduce the synthesis of 25(OH)D3 and cause genetic compensation of CYP2R1.
摘要：
维生素D依赖型病（VDDR）是一组遗传性疾病，其特征是由于活性维生素D缺乏或对活性维生素D无反应而导致的早发性病。VDDR根据相应的致病基因分为几种亚型。在这里，我们描述了中国家系中一种新型的常染色体显性VDDR。先证者和他母亲有严重的骨畸形,牙本质异常,降低血清25羟维生素D3（25（OH）D3）和磷酸盐水平。先证者对高剂量的维生素D3而不是每日低剂量的维生素D3略有反应。全外显子组测序,生物信息学分析，PCR和Sanger测序鉴定了CYP4A22中的无义突变(c.900delG)。过表达的野生型CYP4A22主要定位于内质网和高尔基体,在HepG2细胞中合成25(OH)D3。过表达的CYP4A22突变体增加CYP2R1的表达，并在补充维生素D3的情况下产生很少的25（OH）D3，通过CYP2R1siRNA处理减少。我们得出结论，CYP4A22可作为维生素D3的新型25-羟化酶发挥作用。CYP4A22中的功能缺失突变导致新型VDDR1型（VDDR1C）。CYP2R1和CYP4A22可能对彼此的无义介导的mRNA衰变效应有一定的遗传补偿作用。
CYP4A22的无义突变是在一个维生素D依赖性病和低血清磷酸盐的中国家系中发现的。CYP4A22定位于内质网和高尔基体，并在肝细胞中处理25-羟化酶活性。CYP4A22功能丧失减少25(OH)D3的合成并引起CYP2R1的遗传补偿。
CYP4A22的无义突变是在一个维生素D依赖性病和低血清磷酸盐的中国家系中发现的。CYP4A22定位于内质网和高尔基体，并在肝细胞中处理25-羟化酶活性。CYP4A22功能丧失减少25(OH)D3的合成并引起CYP2R1的遗传补偿。
