Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.
Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.
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DOI：
10.1210/jcem.82.11.4375
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发表时间：
1997-11
期刊：
影响因子：
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通讯作者：
P. Holterhus;H. Brüggenwirth;O. Hiort;A. Kleinkauf-Houcken;K. Kruse;G. Sinnecker;A. Brinkmann
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文献类型：
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作者：
P. Holterhus;H. Brüggenwirth;O. Hiort;A. Kleinkauf-Houcken;K. Kruse;G. Sinnecker;A. Brinkmann
人类雄激素受体（AR）基因的过早终止密码子通常与完全雄激素不敏感综合征相关。然而，我们发现了一个46，XY核型的成年患者，在AR基因的外显子1中携带一个提前终止密码子，表现出部分男性化的迹象：阴毛坦纳4期和阴蒂增大。没有其他家庭成员受到影响。检测到AR基因密码子位置172处的点突变，其用提前终止密码子TGA（蛋白石）替换原始TTA（Leu）。然而，仔细检查测序凝胶，也发现了一个野生型等位基因，表明嵌合现象。此外，由突变诱导的独特AflII识别位点的消除是不完全的，因此证实了患者中突变型和野生型AR等位基因的共存。正常的R1881结合和正常的110/112-kDa AR双联体在Western免疫印迹中通过证明野生型AR在患者生殖器皮肤成纤维细胞中的表达巩固了分子遗传学数据。转染分析表明，只有相对较高的质粒浓度携带突变的AR互补DNA导致表达的缩短AR由于下游重新启动在蛋氨酸189。因此，再起始在表型的呈现中不起作用;相反，部分男性化是由于体细胞嵌合体引起的野生型AR的表达引起的。我们的结论是体细胞嵌合体的AR基因可以代表一个重要因素的个人表型转移到一个更高程度的男性化比预期的基因型的突变等位基因单独。
Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient's genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.