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/jc.82.11.3584
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发表时间：
1997-11-01
影响因子：
5.8
通讯作者：
Brinkmann, AO
中科院分区：
文献类型：
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作者：
Holterhus, PM;Bruggenwirth, HT;Brinkmann, AO
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有关。然而，我们发现了一名46，XY核型的成年患者，该患者携带AR基因外显子1的提前终止密码子，表现出部分男性化的迹象：阴毛黄褐色阶段4和阴蒂增大。没有其他家庭成员受到影响。检测到AR基因第172位密码子的点突变，将原来的TTA(Leu)替换为提前终止密码子TGA(Opal)。然而，对测序凝胶的仔细检查也发现了一种野生型等位基因，表明存在嵌合体。此外，由突变引起的独特的AflII识别位点的消除是不完整的，因此证实了患者中存在突变型和野生型AR等位基因。在Western免疫印迹中，正常的R1881结合和正常的110/112 kDa AR双联通过证明患者生殖器皮肤成纤维细胞中野生型AR的表达，巩固了分子遗传学数据。转染分析表明，只有携带突变的AR互补DNA的相对较高的质粒浓度才会导致缩短的AR的表达，这是由于蛋氨酸189的下游重新启动。因此，重新启动并不对表型的表现起作用；相反，部分雄性化是由于体细胞嵌合体导致野生型AR的表达引起的，我们得出结论，AR基因的体细胞嵌合体可以通过将其转移到比仅由突变等位基因的基因所预期的更高的男性化程度来代表个体表型的重要因素。
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 wildtype 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 wildtype 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.