Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease
Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease
复制标题
DOI：
10.1136/jmg.39.2.91
复制
发表时间：
2002-02-01
影响因子：
4
通讯作者：
Van Hul, W
中科院分区：
文献类型：
--
作者：
Balemans, W;Patel, N;Van Hul, W
Van Buchem 病是一种常染色体隐性骨骼发育不良，其特征是全身骨骼过度生长，主要发生在颅骨和下颌骨。大多数患者会出现面神经麻痹、视神经萎缩和听力受损等临床并发症。这些特征与硬化症非常相似，这两种情况仅通过硬化症中出现的手部畸形和身材高大来区分。利用扩展的荷兰近交 van Buchem 家族和两个近交硬化症家族，我们将两种疾病基因映射到染色体 17q12-q21 上的同一区域，支持 van Buchem 病和硬化症是由同一基因突变引起的假设。在之前的一项研究中，我们从连锁间隔中定位克隆了一个名为 SOST 的新基因，并在硬化症患者的 SOST 基因中发现了三种不同的纯合突变，导致潜在蛋白质功能丧失。本研究的重点是鉴定 van Buchem 家族所有患者中的 52 kb 缺失。该缺失由 Alu 序列之间的同源重组产生，起始于 SOST 基因下游约 35 kb。由于没有发现删除区域内存在基因的证据，我们假设删除的存在通过顺式调节作用或位置效应导致SOST基因转录的下调。
Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOSTgene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.