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资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。对于2006年的这个新项目，我们最近从康奈尔大学（Cornell Universtiy）的Vicki Meyers-Wallen博士那里获得了XX性逆转犬的繁殖菌落。 在XX性逆转中，受影响的个体具有正常的雌性核型（46，XX），没有Y染色体，但在性腺中发展了睾丸组织。受影响的个体出现睾丸（XX雄性）或卵形（XX真实雌雄同体）。一些XX雄性具有确定基因sry的睾丸的Y到常染色体易位。然而，在Sry阴性XX性逆转中，受影响的个体没有Y染色体，也没有SRY基因。 XX雄性的频率约为20,000人的分娩中的1个，10-20％为sry阴性。这些患者大多数的睾丸诱导原因仍然无法解释，因为仅在一种零星病例中发现了XX雄性的特定遗传缺陷，并且一个患有连锁皮肤疾病的家庭。此外，XX真正的Hermaphrodites会发展出卵子，在某些家庭中以及在缺乏XX男性的家庭中作为XX男性的兄弟姐妹出现。这些个体中睾丸诱导的机制仍然未知。该疾病的分子基础的表征将增加我们对睾丸诱导的理解，并为性确定疾病提供诊断测试。由于疾病并不常见，家庭大小很小，并且遗传异质性的可能性很大，因此很难识别人类中的这种基因。动物模型缺乏这些缺点。 性别逆转性特征的犬种谱系与家族性sry阴性xxsr非常相似，其中xx男性和xx true hermaphrodites作为完整的兄弟姐妹出现。与人类一样，犬XX雄性会出现双侧睾丸，而xx真正的雌雄同体会发展出双侧卵形。两者都没有正常的雌性核型（78，XX），并且没有Shouther印迹，并具有全长的犬Sry探针和聚合酶链与犬类特异性SRY底漆的反应。致病基因尚不清楚，但是使用链接不平衡分析和微卫星标记物进行了良好的映射，在犬种血统中鉴定了一个连接的2 MB区域。迄今为止，结果支持一种新型的病因学基因作为该模型的病因，并且正在研究候选基因。 犬模型比其他动物模型具有多个优点。转基因小鼠对研究已知基因很有用，但是缺乏SRY阴性XXSR的天然小鼠模型表明，小鼠可能不是这种特定疾病的选择模型。正常犬类胚胎性腺中的基因表达与人类和家养动物相似，在与小鼠不同的关键基因的时间和空间表达中，与小鼠不同。因此，犬模型是哺乳动物性别确定的代表性模型，并且比其他家养动物具有优势，因为它可以每窝产生多个胚胎。此外，可以使用犬分子工具（7倍犬基因组序列，SNP图）来帮助位置克隆并在胚胎性腺性别确定期间定义基因表达模式。因此，这种疾病的犬模型是新型基因发现和记录其在哺乳动物性别确定中作用的分子机制的重要模型。 - -