A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1.
BACKGROUND
Mutations in the CYP27B1 gene, which encodes vitamin D 1alpha-hydroxylase, are the genetic basis for vitamin D-dependent rickets type 1 (VDDR-I).


OBJECTIVE
The aim of this study was to investigate the CYP27B1 mutation in a large family with VDDR-I and characterize the genotype-phenotype correlation.


METHODS
The index patient was a 23-yr-old female who had a progressive form of rickets and growth retardation since the age of 9 months. Laboratory data showed hypocalcemia, low urine calcium, hypophosphatemia, high serum alkaline phosphatase, elevated PTH, and low serum 1,25-dihydroxyvitamin D(3). Her parents were healthy first-degree cousins, and two of her 12 siblings were affected with similar but milder rickets. Three other siblings were asymptomatic but had biochemical evidence of the disease. The entire coding region of the CYP27B1 gene was sequenced, and the mutation was characterized by functional studies.


RESULTS
We found a novel biallelic c.305G>A sequence variation at codon 102, changing amino acid from glycine to glutamic acid (G102E) in the patient and five affected siblings, whereas a monoallelic c.305G>A variation was present in the mother and five nonaffected siblings. This variation was not present in 100 population controls. Expression of this mutant in CHO cells revealed an 80% reduction in the 1alpha-hydroxylase activity as compared to wild-type activity.


CONCLUSIONS
A novel mutation in the CYP27B1 gene was found in patients with VDDR-I. This mutation resulted in a significant reduction in 1alpha-hydroxylase activity. The residual enzymatic activity may account for the mild phenotype presentation in some affected members.
Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
Ali S
AS
Alzahrani
Minjing
M
Zou
Essa Y
EY
Baitei
Omalkhaire M
OM
Alshaikh
Roua A
RA
Al-Rijjal
Brian F
BF
Meyer
Yufei
Y
Shi
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005190:Family; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D012279:Rickets / Q000235:genetics*; D014807:Vitamin D / Q000502:physiology; D055815:Young Adult
D014807:Vitamin D; D018698:Glutamic Acid; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005998:Glycine