Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome
Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome
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DOI：
10.1038/sj.ejhg.5201303
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发表时间：
2005-02-01
影响因子：
5.2
通讯作者：
Schwartz, CE
中科院分区：
文献类型：
--
作者：
Abidi, FE;Cardoso, C;Schwartz, CE
Chudley-Lowry 综合征（ChLS，MIM 309490）是一种 X 连锁隐性遗传病，其特征为中度至重度智力低下、身材矮小、轻度肥胖、性腺功能减退，以及以鼻梁凹陷、鼻孔前倾、倒 V 形上唇和巨大口为特征的独特面部特征。最初的查德利-洛瑞家族由两代三名受影响的男性组成。连锁分析将该基因定位于一个较大的区间，Xp21-Xq26，并且证明专性载体具有高度偏斜的 X 失活。与 ATR-X 综合征患者一致的临床表型、女性携带者中偏斜的 X 失活模式以及包括 Xq13.3 条带的作图区间相结合，促使我们考虑 XNP/ATR-X 基因与该综合征有关。通过 RT-PCR 分析，我们筛选了整个 XNP/ATR-X 基因，发现外显子 2 (c.109C>T) 发生突变，在第 37 位 (p.R37X) 处产生终止密码子。使用针对 XNP/ATR-X 的特异性单克隆抗体进行的蛋白质印迹和免疫细胞化学分析表明，尽管终止密码子过早，但该蛋白仍存在于一名受影响男性的淋巴母细胞中。为了解释这些不一致的结果，我们进一步分析了 XNP/ATR-X 基因的 50 区域，发现了三个替代转录本，它们的不同之处在于是否存在外显子 2 以及外显子 1 的长度。我们的数据表明 ChLS 与 ATR-X 综合征具有等位基因，其严重程度较低的表型是由于某些 XNP/ATR-X 蛋白的存在。
The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C>T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 50 region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.