Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A

• Published in: Clinical endocrinology (Oxford) 2012-09, Vol.77 (3), p.363-369
• Main Authors: Durmaz, Erdem, Zou, Minjing, Al-Rijjal, Roua A., Bircan, İffet, Akçurin, Sema, Meyer, Brian, Shi, Yufei
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; Adolescent; Adult; Age; Base Sequence; Biological and medical sciences; Calcium (blood); Child; Child, Preschool; DNA Mutational Analysis; Endocrinopathies; Enzymes; Exons; Familial Hypophosphatemic Rickets; Female; Fundamental and applied biological sciences. Psychology; Genetic analysis; Genetic Association Studies; Hereditary diseases; Humans; Infant; Introns; Language; Male; Medical sciences; Metabolic diseases; Metabolism, Inborn Errors - enzymology; Metabolism, Inborn Errors - genetics; Middle Aged; Molecular Sequence Data; Mutagenesis, Insertional; Mutation; Nonsense mutation; Other nutritional diseases (malnutrition, nutritional and vitamin deficiencies...); Rickets - enzymology; Rickets - genetics; RNA Splice Sites - genetics; Seizures; Turkey; Vertebrates: endocrinology; Vitamin D-dependent rickets; Vitamins; Young Adult
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2012.04394.x

Summary Context Vitamin D‐dependent rickets type 1A (VDDR‐IA, OMIM 264700) is a rare autosomal recessive disorder and is caused by mutations in the CYP27B1 gene. Objectives We aim to investigate CYP27B1 mutation in seven patients from four separate families and characterize the genotype–phenotype correlation. Methods The entire coding region of the CYP27B1 gene was sequenced, and genotype–phenotype correlation among patients was assessed. Results Sequencing analysis identified biallelic CYP27B1 mutations in all patients and monoallelic mutations in their parents. One patient from the first family was compound heterozygous for c.1166G>A (p.Arg389His) and a novel nonsense mutation c.1079 C>A (p.Ser360*). Two patients from the second family were homozygous for a novel splice donor site mutation in intron 1 (c.195 + 2 T>G), causing partial retention of the intron and a shift in the reading frame. Both novel mutations lead to the complete loss of vitamin D1α‐hydroxylase activity. Four patients from families 3 and 4 were homozygous for a previously reported duplication mutation in exon 8 (1319–1325dupCCCACCC, Phe443Profs*24). Interestingly, one patient who was presented with severe hypocalcaemia and seizures at 4 months of age as a result of Phe443Profs*24 has improved spontaneously since 11 years of age and does not need regular treatment. Her laboratory tests showed normal serum calcium and 1,25(OH)2D after refusing to take medication for 12 months. Conclusions There is a good genotype–phenotype correlation in VDDR‐IA. However, some patients may recover from the loss of CYP27B1 function, probably due to 1α‐hydroxylase activity exerted by a non‐CYP27B1 enzyme.