CYP27B1 – Vitamin D-Dependent Rickets Type 1

CYP27B1 encodes the mitochondrial 25-hydroxyvitamin D₃ 1α-hydroxylase, the enzyme catalyzing conversion of 25(OH)D to active 1,25(OH)₂D. Biallelic loss-of-function variants cause Vitamin D-dependent rickets type 1, an autosomal recessive disorder characterized by early‐onset rickets, hypocalcemia, hypotonia, and growth failure.

Mode of inheritance is autosomal recessive with well‐documented co-segregation of pathogenic CYP27B1 alleles. Over 30 unrelated probands from >20 families have been reported (PMID:20534770, PMID:26982175). Segregation analysis identifies at least 19 additional affected relatives across multiple pedigrees (PMID:26982175).

The allelic spectrum exceeds 50 distinct variants, including missense, nonsense, splice‐site, and frameshift mutations. A recurrent founder splice donor variant c.195+2T>G occurs in 10 Turkish patients, and the duplication 1319_1325dupCCCACCC (p.Phe443ProfsTer24) is noted in multiple lineages (PMID:26982175).

Functional assays demonstrate abolished 1α-hydroxylase activity for R107His, Gly125Glu, Arg335Pro, and Pro382Ser in recombinant E. coli systems (PMID:10518789), and the missense c.305G>A (p.Gly102Glu) retains only ~20% activity in CHO cells (PMID:20534770). Structural modeling and luciferase‐based assays confirm H441Tyr and R459Leu disrupt adrenodoxin binding, abolishing enzyme function (PMID:27399352).

Clinically, patients present with hypocalcemia, hypophosphatemia, tetany, rickets, growth delay, hypotonia, pathologic fractures, dental enamel hypoplasia, and amelogenesis imperfecta. Calcitriol therapy normalizes biochemical parameters and promotes skeletal and dental recovery (PMID:12789152).

Conflicting associations with multiple sclerosis have been refuted by large case–control cohorts showing no increased risk among heterozygous carriers (PMID:23444327).

Collectively, genetic and experimental evidence support a Definitive gene–disease association. Early molecular diagnosis informs life-saving calcitriol replacement and anticipatory dental management.

Key Take-home: CYP27B1 sequencing in infants with early‐onset rickets and hypocalcemia directs precise calcitriol therapy and tailored dental interventions.

References

• Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics • 2003 • Oral and dental manifestations of vitamin D-dependent rickets type I: report of a pediatric case. PMID:12789152
• The Journal of clinical endocrinology and metabolism • 2010 • A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1. PMID:20534770
• European journal of biochemistry • 1999 • Enzymatic properties of human 25-hydroxyvitamin D₃ 1alpha-hydroxylase coexpression with adrenodoxin and NADPH-adrenodoxin reductase in Escherichia coli. PMID:10518789
• The Journal of clinical endocrinology and metabolism • 2016 • Vitamin D-Dependent Rickets Type 1 Caused by Mutations in CYP27B1 Affecting Protein Interactions With Adrenodoxin. PMID:27399352
• Hormone research in paediatrics • 2016 • Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I. PMID:26982175
• The New England journal of medicine • 1998 • Inactivating mutations in the 25-hydroxyvitamin D₃ 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. PMID:9486994
• Annals of neurology • 2013 • No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. PMID:23444327

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