Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
J Clin Endocrinol Metab. 2010 Sep;95(9):4176-83. doi: 10.1210/jc.2009-2278. Epub 2010 Jun 9.
Mutations in the CYP27B1 gene, which encodes vitamin D 1alpha-hydroxylase, are the genetic basis for vitamin D-dependent rickets type 1 (VDDR-I).
The aim of this study was to investigate the CYP27B1 mutation in a large family with VDDR-I and characterize the genotype-phenotype correlation.
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.
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.
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.
编码维生素 D1α-羟化酶的 CYP27B1 基因突变是维生素 D 依赖性佝偻病 1 型（VDDR-I）的遗传基础。
本研究旨在调查一个大型 VDDR-I 家族中的 CYP27B1 突变，并阐明基因型-表型相关性。
指数患者是一名 23 岁女性，自 9 个月大以来患有进行性佝偻病和生长迟缓。实验室数据显示低钙血症、尿钙低、低磷血症、血清碱性磷酸酶升高、甲状旁腺激素升高和血清 1,25-二羟维生素 D(3)低。她的父母是健康的表亲，她的 12 个兄弟姐妹中有 2 个受到类似但较轻的佝偻病影响。另外 3 个兄弟姐妹无症状，但有该疾病的生化证据。CYP27B1 基因的整个编码区均进行了测序，并通过功能研究对突变进行了特征描述。
我们在患者和 5 名受影响的兄弟姐妹中发现了一种新的双等位基因 c.305G>A 序列变异，导致密码子 102 处的甘氨酸突变为谷氨酸（G102E），而母亲和 5 名未受影响的兄弟姐妹中存在单等位基因 c.305G>A 变异。这种变异在 100 名人群对照中不存在。该突变在 CHO 细胞中的表达导致 1α-羟化酶活性降低 80%，与野生型活性相比。
在 VDDR-I 患者中发现了 CYP27B1 基因的一种新突变。该突变导致 1α-羟化酶活性显著降低。残留的酶活性可能解释了一些受影响成员的轻度表型表现。
