Sex-determining gene(s) on distal 9p: Clinical and molecular studies in six cases
Sex-determining gene(s) on distal 9p: Clinical and molecular studies in six cases
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DOI：
10.1210/jc.85.9.3094
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发表时间：
2000-09-01
影响因子：
5.8
通讯作者：
Ogata, T
中科院分区：
文献类型：
--
作者：
Muroya, K;Okuyama, T;Ogata, T
我们报告的临床和分子研究结果，在五个核型男性（例1-5）和一个核型女性（例6）与远端9 p单体。例1-3和例6为女性外生殖器，例4外生殖器不清，例5为男性外生殖器，左侧隐睾，右侧阴囊内睾丸。例3和例4在性腺切除术时的性腺探查显示，例3为左侧条纹状性腺和右侧无性腺症，例4为双侧睾丸发育不全。病例1-4和6的内分泌研究显示，病例1、3和6有明确的原发性性腺功能减退症，基础FSH水平分别为54、39和41 IU/L，而病例2有严重营养不良，基线值不明显，病例4睾丸功能相当好。荧光原位杂交和微卫星分析表明，所有的情况下有半合子的9 p性别决定区远端D9 S1779，与候选性别决定基因DMRT 1和DMRT 2的异常9号染色体的损失。对病例1-4和6进行序列分析，结果显示，它们的DMRT 1各外显子和DMRT 2 DM结构域的序列均正常，位于正常的9号染色体上，病例1-4的SRY序列均正常。这些结果进一步支持了在远端9 p上存在性别决定基因，并支持DMRT 1和/或DMRT 2是性别决定基因的可能性。此外，由于9 p性别决定区的半合子性与核型雄性中从激动剂作用到睾丸形成的广泛的性腺发生相关，并且与原发性性腺功能减退相关，而与核型性别无关，因此推断9 p性别决定基因的单倍不足主要阻碍中性性腺的形成，导致核型雄性中不同程度的有缺陷的睾丸形成和核型雌性中受损的卵巢形成。
We report on clinical and molecular findings in five karyotypic males (cases 1-5) and one karyotypic female (case 6) with distal 9p monosomy. Cases 1-3 and 6 had female external genitalia, case 4 showed ambiguous external genitalia, and case 5 exhibited male external genitalia with left cryptorchidism and right intrascrotal testis. Gonadal explorations at gonadectomy in cases 3 and 4 revealed that case 3 had left streak gonad and right agonadism, and case 4 had bilateral hypoplastic testes. Endocrine studies in cases 1-4 and 6 showed that cases 1, 3, and 6 had definite primary hypogonadism, with basal FSH levels of 54, 39, and 41 IU/L, respectively, whereas case 2 with severe malnutrition was unremarkable for the baseline values, and case 4 had fairly good testicular function. Fluorescence in situ hybridization and microsatellite analyses demonstrated that all cases had hemizygosity of the 9p sex-determining region distal to D9S1779, with loss of the candidate sex-determining genes DMRT1 and DMRT2 from the abnormal chromosome 9. Sequence analysis in cases 1-4 and 6 showed that they had normal sequences of each exon of DMRT1 and the DM domain of DMRT2 on the normal chromosome 9, and that cases 1-4 had normal SRY sequence. The results provide further support for the presence of a sex-determining gene(s) on distal 9p and favor the possibility of DMRT1 and/or DMRT2 being the sex-determining gene(s). Furthermore, as hemizygosity of the 9p sex-determining region was associated with a wide spectrum of gonadogenesis from agonadism to testis formation in karyotypic males and with primary hypogonadism regardless of karyotypic sex, it is inferred that haploinsufficiency of the 9p sex-determining gene(s) primarily hinders the formation of indifferent gonad, leading to various degrees of defective testis formation in karyotypic males and impaired ovary formation in karyotypic females.