Institute for Human Genetics, University-Clinic Erlangen, D-91054 Erlangen, Germany.
Gene. 2013 Apr 15;518(2):267-72. doi: 10.1016/j.gene.2013.01.030. Epub 2013 Jan 30.
Congenital genital malformations occurring in the female population are estimated to be 5 per 1000 and associate with infertility, abortion, stillbirth, preterm delivery and other organ abnormalities. Complete aplasia of the uterus, cervix and upper vagina (Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome) has an incidence of 1 per 4000 female live births. The molecular etiology of congenital genital malformations including MRKH is unknown up to date. The homeobox (HOX) genes HOXA10 and HOXA13 are involved in the development of human genitalia. In this investigation, HOXA10 and HOXA13 genes of 20 patients with the MRKH syndrome, 7 non-MRKH patients with genital malformations and 53 control women were sequenced to assess for DNA variations. A total of 14 DNA sequence variations (10 novel and 4 known) within exonic and untranslated regions were detected in HOXA10 and HOXA13 among our cohorts. Four HOXA10 and two HOXA13 DNA sequence variations were found solely in patients with genital malformations. In addition to mutations resulting in synonymous amino acid substitutions, in the HOXA10 gene a missense mutation was identified and predicted by computer analysis as probably damaging to protein function in two non-MRKH patients, one with a bicornate and the other patient with a septated uterus. A novel exonic HOXA10 cytosine deletion was also identified in a non-MRKH patient with a septate uterus and renal malformations resulting in a premature stop codon and loss of the homeodomain helix 3/4. This cytosine deletion and the missense mutation in HOXA10 were analysed by real time PCR and sequencing, respectively, in two additional larger cohorts of 103 patients with MRKH and 109 non-MRKH patients with genital malformations. No other patients were found with the cytosine deletion however one additional patient was identified regarding the missense mutation. Rare DNA sequence variations in the HOXA10 gene could contribute to the misdevelopment of female internal genitalia.
据估计，女性人群中先天性生殖器畸形的发病率为每 1000 例中有 5 例，这些畸形与不孕、流产、死产、早产和其他器官异常有关。子宫、宫颈和上阴道完全发育不全（Mayer-Rokitansky-Küster-Hauser (MRKH) 综合征）的发病率为每 4000 例女性活产儿中有 1 例。到目前为止，包括 MRKH 在内的先天性生殖器畸形的分子病因尚不清楚。同源盒 (HOX) 基因 HOXA10 和 HOXA13 参与了人类生殖器的发育。在这项研究中，对 20 名 MRKH 综合征患者、7 名非 MRKH 生殖器畸形患者和 53 名对照女性的 HOXA10 和 HOXA13 基因进行了测序，以评估 DNA 变异。在我们的队列中，HOXA10 和 HOXA13 基因的外显子和非翻译区共检测到 14 种 DNA 序列变异（10 种新的和 4 种已知的）。在仅患有生殖器畸形的患者中发现了 4 种 HOXA10 和 2 种 HOXA13 DNA 序列变异。除了导致同义氨基酸取代的突变外，在 HOXA10 基因中，还鉴定出一种错义突变，计算机分析预测该突变可能对 2 名非 MRKH 患者的蛋白质功能造成损害，其中 1 名患者的子宫为两角形，另 1 名患者的子宫为纵隔。在一名非 MRKH 患者中还发现了一种新的外显子 HOXA10 胞嘧啶缺失，该患者患有纵隔子宫和肾脏畸形，导致提前终止密码子和同源结构域螺旋 3/4 的缺失。该胞嘧啶缺失和 HOXA10 中的错义突变分别通过实时 PCR 和测序在另外两个更大的 MRKH 患者队列（103 例）和 109 例非 MRKH 生殖器畸形患者队列中进行了分析。然而，没有发现其他患者存在胞嘧啶缺失，但发现了 1 例患者存在错义突变。HOXA10 基因中的罕见 DNA 序列变异可能导致女性内生殖器发育异常。
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