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.
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 reduces the synthesis of 25(OH)D3 and causes genetic compensation of CYP2R1.

BACKGROUND: Coronary heart disease (CHD) has become a worldwide public health problem. Genetic factors are considered important risk factors for CHD. The aim of this study was to explore the correlation between CYP4A22 gene polymorphism and CHD susceptibility in the Chinese Han population.
METHODS: We used SNPStats online software to complete the association analysis among 962 volunteers. False-positive report probability analysis was used to confirm whether a positive result is noteworthy. Haploview software and SNPStats were used for haplotype analysis and linkage disequilibrium. Multi-factor dimensionality reduction was applied to evaluate the interaction between candidate SNPs.
RESULTS: In overall and some stratified analyses (male, age ≤ 60 years or CHD patients complicated with hypertension), CYP4A22-rs12564525 (overall, OR = 0.83, p-value is 0.042) and CYP4A22-rs2056900 (overall, OR = 1.22, p-value is 0.032) were associated with the risk of CHD. CYP4A22-4926581 was associated with increased CHD risk only in some stratified analyses. FPRP indicated that all positive results in our study are noteworthy findings. In addition, MDR showed that the single-locus model composed of rs2056900 is the best model for predicting susceptibility to CHD.
CONCLUSIONS: There are significant associations between susceptibility to CHD and CYP4A22 rs12564525, and rs2056900.

Cerebral stroke (stroke) is an acute cerebrovascular disease with high incidence and mortality. This study aimed to explore the association between single nucleotide polymorphisms (SNPs) of CYP4A22 and stroke risk in the Chinese Han population.
A total of 550 stroke patients and 545 healthy people were recruited. Four candidate SNPs (rs76011927 T/C, rs12564525 C/T, rs2056900 A/G and rs4926581 T/G) of CYP4A22 were screened. The association between CYP4A22 SNPs and stroke risk was assessed using genetic models and the relationship between SNPs and clinical biochemical indicators was analyzed by one-way analysis of variance (one-way ANOVA).
The overall analysis showed that rs12564525 could significantly reduce stroke risk only under the recessive model (OR = 0.72, 95% CI 0.53-0.99), but rs2056900 and rs4926581 were significantly associated with increased stroke risk under the homozygote (OR = 1.49, 95% CI 1.06-2.09; OR = 1.49, 95% CI 1.06-2.10), heterozygote (OR = 1.49, 95% CI 1.11-2.00; OR = 1.48, 95% CI 1.11-1.99), additive (OR = 1.22, 95% CI 1.03-1.45; OR = 1.22, 95% CI 1.03-1.45) and dominant (OR = 1.49, 95% CI 1.13-1.97; OR = 1.49, 95% CI 1.13-1.96) models (all p < 0.05). Subgroup analyses further indicated that rs2056900 and rs4926581 could significantly increase stroke risk in participants aged >63 years and females. In addition, high-density lipoprotein cholesterol (HDL-C) levels differed considerably among different genotypes of rs12564525, rs2056900 and rs4926581.
This study revealed that CYP4A22 SNPs are associated with stroke risk in the Chinese Han population, and in particular, rs2056900 and rs4126581 have a significant correlation with increased stroke risk.

The human cytochrome P450 (CYP) enzyme CYP4A22 is an orphan CYP with unknown function. Here, through functional expression in fission yeast, we show that CYP4A22 catalyzes fatty acid hydroxylation as well as aliphatic or aromatic hydroxylations of luciferin-based probe substrates. Mechanistic molecular modeling of CYP4A22 suggests that its ω-hydroxylation activity is hampered by a more spacious active site compared to CYP4B1. Substrate recognition via side-chains R96 and R233 is indicated by dynamic three-dimensional pharmacophores (dynophores) derived from molecular dynamics simulations. CYP4A22 activity is inhibited by three unspecific CYP inhibitors. A comparison of CYP4A22*1 (the reference standard sequence) with CYP4A22-WT (the most common allele) revealed that for the four substrates tested the WT-enzyme always had lower activity.