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Clinical and genetic analysis of patients with vitamin D ‐dependent rickets type 1 A
Author(s) -
Durmaz Erdem,
Zou Minjing,
AlRijjal Roua A.,
Bircan İffet,
Akçurin Sema,
Meyer Brian,
Shi Yufei
Publication year - 2012
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2012.04394.x
Subject(s) - exon , nonsense mutation , genotype , medicine , endocrinology , frameshift mutation , hypocalcaemia , genetics , mutation , intron , rickets , missense mutation , biology , genotype phenotype distinction , vitamin d and neurology , microbiology and biotechnology , gene , calcium
Summary Context Vitamin D ‐dependent rickets type 1 A ( 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. A rg389 H is) and a novel nonsense mutation c.1079 C > A (p. S er360*). 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 D 1α‐hydroxylase activity. Four patients from families 3 and 4 were homozygous for a previously reported duplication mutation in exon 8 (1319–1325dup CCCACCC , P he443 P rofs*24). Interestingly, one patient who was presented with severe hypocalcaemia and seizures at 4 months of age as a result of P he443 P rofs*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 ) 2 D 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.