CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI
CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI
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DOI：
10.1093/molehr/6.9.861
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发表时间：
2000-09-01
影响因子：
4
通讯作者：
Trounson, AO
中科院分区：
文献类型：
--
作者：
Cram, DS;Song, B;Trounson, AO
雄激素受体（AR）基因位于X染色体上，含有多态性CAG束。AR中CAG重复序列扩增与男性不育和神经肌肉疾病脊髓延髓肌萎缩症（SBMA）有关。根据孟德尔遗传模式，经卵胞浆内单精子注射（ICSI）治疗的不育男性中中度CAG扩增将垂直传递给雌性后代。如果在男性生殖系中发生重复区的进一步延长，可以想象，更长的扩增也可以通过ICSI传递，并可能导致后代中男性不育和SBMA的发病率增加。为了确定ICSI后父亲AR CAG束的稳定程度，我们比较了92名接受ICSI的男性及其99名ICSI受孕的女儿的AR等位基因中的CAG重复数。通过荧光聚合酶链反应和DNA测序凝胶上分离的扩增产物的基因扫描分析确定AR等位基因中的CAG重复长度。在绝大多数情况下（95/99），我们发现AR CAG束的大小范围从15-28重复在雌性后代中表现出稳定的遗传。然而，在其余的父女对中，预期的遗传模式与CAG扩增的证据不一致。（20-->24; 22-->23）和收缩（26-->18或22）的父本AR等位基因，在ICSI后检测到父亲AR等位基因中CAG突变的低频率与起源于减数分裂DNA复制的性腺嵌合体相一致错误.在一组典型的接受ICSI治疗各种适应症的不育男性中的这些发现倾向于减轻以下担忧：ICSI可能促进AR等位基因的传播，扩大CAG束，并表明第二代儿子的SBMA风险极低。
The androgen receptor (AR) gene is located on the X chromosome and contains a polymorphic CAG tract. CAG repeat expansions in the AR have been associated with male infertility and the neuromuscular disease, spinal bulbar muscular atrophy (SBMA), Based on Mendelian inheritance patterns, moderate CAG expansions in infertile men treated by intracytoplasmic sperm injection (ICSI) would be vertically transmitted to female offspring. Should further elongation of the repeat region occur in the male germline, it is conceivable that longer expansions could also be transmitted by ICSI and may lead to an increased incidence of male infertility and SBMA in succeeding generations. To determine the degree of stability of the paternal AR CAG tract following ICSI, we compared the CAG repeat number in the AR alleles of 92 men presenting for ICSI and their 99 ICSI-conceived daughters. CAG repeat lengths in the AR alleles were determined by fluorescent polymerase chain reaction and Genescan analysis of amplification products separated on DNA sequencing gels. In the vast majority of cases (95 out of 99), we found that the AR CAG tracts ranging in size from 15-28 repeats exhibited stable inheritance in female offspring. However, in the remaining father-daughter pairs, there was a discordance in the expected inheritance pattern with evidence for both CAG expansion (20-->24; 22-->23) and contraction (26-->18 or 22) of the paternal AR allele, The detection of a low frequency of CAG mutation in paternal AR alleles following ICSI would be consistent with gonadal mosaicism originating from meiotic DNA replication errors. These findings in a typical group of infertile men undergoing ICSI for a variety of indications tend to alleviate concerns that: ICSI may promote the transmission of AR alleles with expanded CAG tracts and suggest that the risk of SBMA in second generation sons would be extremely low.