CANINE XX SEX REVERSAL

犬 XX 性别逆转

• 批准号: 7391974
• 负责人: MARK E HASKINS
• 金额: $ 0.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391974
• 关键词: CANINE; XX; SEX; REVERSAL

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For this new project in 2006, we have recently obtained part of the breeding colony of XX sex reversal dogs from Dr. Vicki Meyers-Wallen at Cornell Universtiy. In XX sex reversal, affected individuals have a normal female karyotype (46,XX), and no Y chromosome, yet develop testicular tissue in the gonad. Affected individuals develop testes (XX male) or ovotestes (XX true hermaphrodite). Some XX males have a Y to autosome translocation containing the testis determining gene SRY. However, in SRY-negative XX sex reversal, affected individuals have no Y chromosome and no SRY gene. The frequency of XX males is approximately 1 in 20,000 human births with 10-20% being SRY-negative. The cause of testis induction in the majority of these patients remains unexplained, as a specific genetic defect in XX males has been identified in only one sporadic case and one family with linked cutaneous disease. Additionally, XX true hermaphrodites, which develop ovotestes, occur as siblings of XX males in some families and also within families in which XX males are absent. The mechanism of testis induction in these individuals remains unknown. Characterization of the molecular basis for this disorder would increase our understanding of testis induction and provide diagnostic tests for sex determination disorders. It is difficult to identify such genes in humans since the disorders are uncommon, family sizes are small, and the likelihood of genetic heterogeneity is large. Animal models lack these disadvantages. The canine pedigree segregating the sex reversal trait is strikingly similar to familial SRY-negative XXSR in which XX males and XX true hermaphrodites occur as full siblings. As in humans, canine XX males develop bilateral testes and XX true hermaphrodites develop bilateral ovotestes. Both have a normal female karyotype (78,XX) and Sry is absent, as assayed by Southern blot with a full-length canine Sry probe and polymerase chain reaction with canine specific Sry primers. The causative gene is unknown, but a linked 2 Mb region has been identified in the canine pedigree segregating this trait, using linkage disequilibrium analysis and fine mapping with microsatellite markers. Results to date support a novel etiologic gene as causative in this model, and candidate genes are under investigation. The canine model has several advantages over other animal models. Transgenic mice have been useful to study known genes, but the lack of naturally-occurring mouse models of Sry-negative XXSR suggests that the mouse may not be the model of choice for this particular disorder. Gene expression in normal canine embryonic gonads is similar to that of humans and domestic animals in temporal and spatial expression of key genes involved in sex determination, unlike the mouse. Thus, the canine model is a representative model of mammalian sex determination and has an advantage over other domesticated animals in that it can produce multiple embryos per litter. Furthermore, canine molecular tools (7x canine genome sequence, SNP map) are available to assist positional cloning and to define gene expression patterns during embryonic gonadal sex determination. Thus, the canine model of this disorder is an important model for novel gene discovery and documentation of the molecular mechanism of their role in mammalian sex determination. --

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。对于 2006 年的这个新项目，我们最近从康奈尔大学的 Vicki Meyers-Wallen 博士那里获得了部分 XX 性逆转狗的繁殖群体。 在XX性逆转中，受影响的个体具有正常的女性核型（46,XX），并且没有Y染色体，但性腺中发育有睾丸组织。受影响的个体发育出睾丸（XX 男性）或卵睾（XX 真正的雌雄同体）。一些 XX 男性具有 Y 至常染色体易位，其中含有睾丸决定基因 SRY。然而，在SRY阴性的XX性逆转中，受影响的个体没有Y染色体，也没有SRY基因。 XX 男性的发生率约为每 20,000 名新生儿中就有 1 人，其中 10-20% 为 SRY 阴性。大多数患者睾丸诱导的原因仍无法解释，因为仅在一名散发病例和一个患有相关皮肤病的家庭中发现了 XX 男性的特定遗传缺陷。此外，发育出卵睾的 XX 真正雌雄同体，作为 XX 雄性的兄弟姐妹出现在一些家庭中，也存在于不存在 XX 雄性的家庭中。这些个体的睾丸诱导机制仍不清楚。这种疾病的分子基础的表征将增加我们对睾丸诱导的理解，并为性别决定障碍提供诊断测试。由于这种疾病并不常见，家庭规模较小，并且遗传异质性的可能性很大，因此很难在人类中识别此类基因。动物模型没有这些缺点。 区分性逆转特征的犬科动物谱系与家族性 SRY 阴性 XXSR 惊人相似，其中 XX 只雄性和 XX 只真正的雌雄同体作为亲兄弟姐妹出现。与人类一样，犬 XX 雄性发育双侧睾丸，XX 真正雌雄同体发育双侧卵睾。两者均具有正常的雌性核型 (78,XX)，并且通过使用全长犬 Sry 探针的 Southern 印迹和使用犬特异性 Sry 引物的聚合酶链反应进行测定，Sry 不存在。致病基因尚不清楚，但通过连锁不平衡分析和微卫星标记精细作图，在犬科动物谱系中鉴定出了一个 2 Mb 连锁区域，分离了该性状。迄今为止的结果支持一种新的病因基因是该模型的致病基因，候选基因正在研究中。 与其他动物模型相比，犬模型有几个优点。转基因小鼠可用于研究已知基因，但缺乏天然存在的 Sry 阴性 XXSR 小鼠模型表明，小鼠可能不是这种特殊疾病的首选模型。与小鼠不同，正常犬胚胎性腺中参与性别决定的关键基因的时间和空间表达与人类和家畜的基因表达相似。因此，犬模型是哺乳动物性别决定的代表性模型，并且比其他驯养动物具有优势，因为它每窝可以产生多个胚胎。此外，犬分子工具（7x 犬基因组序列、SNP 图）可用于协助定位克隆并定义胚胎性腺性别决定过程中的基因表达模式。因此，这种疾病的犬模型是新基因发现和记录其在哺乳动物性别决定中作用的分子机制的重要模型。 --