A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda
A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda
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DOI：
10.1086/320594
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发表时间：
2001-06-01
影响因子：
9.8
通讯作者：
Gecz, J
中科院分区：
文献类型：
--
作者：
Tiller, GE;Hannig, VL;Gecz, J
迟发性脊椎骨骺发育不良（SEDL）是一种遗传异质性疾病，其特征是轻度至中度身材矮小和早发性骨关节炎。常染色体和X连锁形式都有描述。在其他地方，我们已经报道了X连锁隐性形式的基因的鉴定，其映射到Xp22.2。我们现在报告两个不相关的SEDL家族中外显子跳跃突变（IVS 3 +5G -->A在内含子3剪接供体位点）的特征。使用逆转录酶（RT）-PCR，我们证明了突变导致开放阅读框的前31个密码子的消除。在120条对照X染色体中未检测到该突变。来自患有SEDL并携带这种突变的成人的关节软骨包含具有丰富的高尔基复合体和扩张的粗面内质网（ER）的软骨细胞。使用小鼠/人细胞杂交的RT-PCR实验显示SEDL基因逃避X失活。SEDL基因的同源物包括在19号染色体上转录的retropylidogene，以及在小鼠、大鼠、果蝇、秀丽隐杆线虫和酿酒酵母中表达的基因。后者的同源物，p20，有一个假定的作用，从ER囊泡运输到高尔基复合体。这些数据表明，SEDL突变可能会扰乱细胞内途径，这是重要的软骨稳态。
Spondyloepiphyseal dysplasia tarda (SEDL) is a genetically heterogeneous disorder characterized by mild-to-moderate short stature and early-onset osteoarthritis. Both autosomal and X-linked forms have been described. Elsewhere, we have reported the identification of the gene for the X-linked recessive form, which maps to Xp22.2. We now report characterization of an exon-skipping mutation (IVS3+5G -->A at the intron 3 splice-donor site) in two unrelated families with SEDL. Using reverse transcriptase (RT)-PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame. The mutation was not detected in 120 control X chromosomes. Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER). RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation. Homologues of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila melanogaster Caenorhabditis elegans, and Saccharomyces cerevisiae. The latter homologue, p20, has a putative role in vesicular transport from ER to Golgi complex. These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis.