Kim Chan Jong, Kaplan Larry E, Perwad Farzana, Huang Ningwu, Sharma Amita, Choi Yong, Miller Walter L, Portale Anthony A
Department of Pediatrics, University of California, San Francisco, 533 Parnassus Avenue, Box 0748, Room U-585, San Francisco, California 94143-0748, USA.
J Clin Endocrinol Metab. 2007 Aug;92(8):3177-82. doi: 10.1210/jc.2006-2664. Epub 2007 May 8.
Vitamin D 1alpha-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-hydroxylase, CYP27B1) gene. The human gene encoding the 1alpha-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns. We previously isolated the human 1alpha-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1alpha-hydroxylase deficiency. OBJECTIVES, PATIENTS, AND METHODS: We analyzed the 1alpha-hydroxylase gene of 10 patients, five from Korea, two from the United States, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1,25-dihydroxyvitamin D(3).
Direct sequencing identified the responsible 1alpha-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included a nonsense mutation in exon 6, substitution of adenine for guanine (2561G-->A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C-->T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G-->A) causing a frameshift.
Mutations in the 1alpha-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1alpha-hydroxylase mutations and the clinical findings of 1alpha-hydroxylase deficiency.
维生素D 1α-羟化酶缺乏症，也称为1型维生素D依赖性佝偻病，是一种常染色体隐性疾病，其特征为佝偻病伴低钙血症的早期发作，由25-羟维生素D 1α-羟化酶（1α-羟化酶，CYP27B1）基因突变引起。编码1α-羟化酶的人类基因长度为5kb，位于12号染色体上，由9个外显子和8个内含子组成。我们之前分离出了人类1α-羟化酶cDNA和基因，并在25例1α-羟化酶缺乏症患者中鉴定出19种不同的突变。
目的、患者和方法：我们分析了10例患者的1α-羟化酶基因，其中5例来自韩国，2例来自美国，1例分别来自阿根廷、丹麦和摩洛哥，所有患者均来自非近亲家庭。每位患者均有佝偻病、低钙血症以及血清1,25-二羟维生素D(3)浓度降低的临床和影像学特征。
直接测序在20个等位基因中的19个中鉴定出了导致病变的1α-羟化酶基因突变。鉴定出4种新突变和4种已知突变。新突变包括外显子6中的无义突变，腺嘌呤取代鸟嘌呤（2561G→A），在密码子328处产生终止信号；外显子9中腺嘌呤缺失（3922delA）导致移码；外显子2中胸腺嘧啶取代胞嘧啶（1031C→T）导致氨基酸改变P112L；以及一个剪接位点突变，内含子7第一个核苷酸中的腺嘌呤取代鸟嘌呤（IVS7+1 G→A）导致移码。
先前在44例患者中鉴定出了1α-羟化酶基因突变，我们在此基础上又增加了10例。研究表明1α-羟化酶突变与1α-羟化酶缺乏症的临床发现之间存在密切关联。
