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CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C)
Xiaohong Duan1, Yanli Zhang1, Taoyun Xu1
1State 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.
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 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.
Insights
Researchers identified a new genetic cause of vitamin D-dependent rickets (VDDR) linked to the CYP4A22 gene. Mutations in this gene disrupt vitamin D activation, leading to a novel VDDR type 1C.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Vitamin D-dependent rickets (VDDR) comprises genetic disorders causing early-onset rickets due to impaired vitamin D activation or response.
- VDDR is classified into subtypes based on causative genes, with known types involving VDR, CYP2R1, and CYP27B1.
Purpose of the Study:
- To identify the genetic basis of a novel form of autosomal dominant VDDR in a Chinese family.
- To elucidate the function of the identified gene in vitamin D metabolism.
Main Methods:
- Whole-exome sequencing and subsequent bioinformatic analysis, PCR, and Sanger sequencing were employed.
- Functional studies involved overexpression of wild-type and mutant CYP4A22 in HepG2 cells and siRNA-mediated knockdown of CYP2R1.
Main Results:
- A nonsense mutation (c.900delG) in the CYP4A22 gene was identified as the cause of VDDR in the studied pedigree.
- Overexpressed wild-type CYP4A22 localized to the endoplasmic reticulum and Golgi apparatus, synthesizing 25-hydroxyvitamin D3 (25[OH]D3).
- The CYP4A22 mutant impaired 25[OH]D3 synthesis and affected CYP2R1 expression, suggesting a role in vitamin D hydroxylation.
Conclusions:
- CYP4A22 acts as a novel 25-hydroxylase for vitamin D3.
- Loss-of-function mutations in CYP4A22 cause a new subtype of VDDR, termed VDDR type 1C (VDDR1C).
- CYP2R1 and CYP4A22 may exhibit genetic compensation mechanisms in response to each other's expression levels.
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