State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology, Clinic of Oral Rare Diseases and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, 145 West Changle Road, Xi'an 710032, China.
J Bone Miner Res. 2024 Aug 5;39(7):967-979. doi: 10.1093/jbmr/zjae084.
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 a high dose of vitamin D3 instead of a 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.
维生素 D 依赖性佝偻病 (VDDR) 是一组遗传性疾病，其特征为由于活性维生素 D 缺乏或对活化的维生素 D 无反应而导致早发性佝偻病。VDDR 根据相应的致病基因分为几个亚型。在这里，我们描述了一个中国家系中一种新的常染色体显性 VDDR。先证者及其母亲存在严重的骨骼畸形、牙本质异常和血清 25 羟维生素 D3（25[OH]D3）和磷酸盐水平降低。先证者对大剂量维生素 D3 略有反应，而不是每日低剂量维生素 D3。全外显子组测序、生物信息学分析、PCR 和 Sanger 测序鉴定出 CYP4A22（c.900delG）中的无义突变。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 突变体增加了 CYP2R1 的表达，并在补充维生素 D3 时产生很少的 25(OH)D3，而 CYP2R1 siRNA 处理则减少了 25(OH)D3 的产生。我们得出结论，CYP4A22 作为维生素 D3 的一种新的 25-羟化酶发挥作用。CYP4A22 失功能突变导致一种新型的 VDDR1C 型。CYP2R1 和 CYP4A22 可能存在一些遗传补偿，相互作用以应对无义介导的 mRNA 衰变效应。
