Molecular Genetics of Muscular/Neurosensory Models

描述（由申请人提供）：我们最近发现了一种自发性 小鼠突变体，veils（维斯），具有视网膜血管病变，听力损失和 进行性肌肉萎缩，许多人类疾病报告的表型，如 Coat氏病、综合征型和非综合征型先天性听力损失，以及 肌肉萎缩症。我们已经将面纱映射到0.19+/-0.13 cM 在1，072次减数分裂重组杂交中， 关键区域的物理重叠群。部分人类Chrs。2，4q，8， 13，17，18，l9 p和22映射到该区域，其断点尚未确定。 要优雅。有趣的是，面纱有许多，如果不是所有的表型 报道的疾病筋膜肩肱型肌营养不良症la（FSHD）， 第三大最普遍的肌肉萎缩症，影响1/20，000，并映射到人类 Chr. 4q35.此外，一种与发病年龄高度可变相关的神经肌病 图为Chr.l9pl3。面纱是一种潜在的遗传和/或表型模型， 这些疾病。面纱鼠的独特之处还在于， 分层异常，这是一种以前没有报道过的表型， 文学作品 为了了解疾病背后的生物学机制 过程，并确定在不同的生物化学途径， 组织，我们将：（a）定位克隆veils基因，并确定 第二个等位基因myd的突变，并检验表型突变的假设， v/s和myd之间的差异由等位基因异质性解释;（B） 开始在遗传背景中识别可以显著改变 维斯/维斯小鼠的疾病表型;以及（c）检验以下假设： 观察到的表型是发育缺陷的结果，而不是 退化过程 致病基因和动物模型的鉴定是极其困难的。 重要.人类的许多疾病，特别是那些涉及眼睛的疾病，如果 如果发现得足够早，可以治疗以减轻疾病的过程。如果没有 了解了疾病的分子基础， 可以为新的治疗方案提供见解，然后可以使用模型 来测试这些疗法最后，对致病基因的了解， 从而了解在维持正常的 功能和生理的有机体，也许，可以确定治疗 预防肌肉萎缩、视力或听力损失的目标。

DESCRIPTION (provided by applicant): We have recently identified a spontaneous mouse mutant, veils (vis), that has retinal vasculopathy, hearing loss and progressive muscle wasting, phenotypes reported for many human diseases, such as Coat's disease, syndromic and non-syndromic congenital hearing loss, and muscular dystrophy, respectively. We have mapped veils to a 0.19+/-0.13 cM interval on mouse Chr. 8 in a 1,072 meiotic recombinant cross and established the physical contig of the critical region. Portions of human Chrs. 2, 4q, 8, 13, 17, 18, l9p and 22 map to this region, the breakpoints of which have yet to be refined. Interestingly, veils has many, if not all of the phenotypes reported for the disease fascioscapulohumeral muscular dystrophy la (FSHD), the third most prevalent muscular dystrophy that affects 1/20,000 and maps to human Chr. 4q35. Also, a neuromyopathy associated with a highly variable age-of-onset maps to Chr. l9pl3. Veils is a potential genetic and/or phenotypic model for these diseases. The veils mouse is also unique in that it shows retinal lamination abnormalities, a phenotype that has not previously been reported in the literature. In order to understand the biological mechanisms that underlie the disease processes and identify the biochemical pathways that are affected in different tissues, we will: (a) positionally clone the veils gene and identify the mutation in the second allele myd and test the hypothesis that the phenotypic differences between v/s and myd are explained by allelic heterogeneity; (b) begin to identify genes in the genetic background that can significantly alter the disease phenotypes of vis/vis mice; and (c) test the hypothesis that the observed phenotypes are the result of developmental defects rather than degenerative processes. Identification of disease causing genes and animal models is extremely important. Many diseases in humans, especially those involving the eye, if identified early enough, can be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights to new treatment regimens and the models can then be used to test those therapeutics. Finally, knowledge of the disease causing genes may lead to an understanding of pathways that are critical in maintaining normal function and physiology of the organism and perhaps, may identify therapeutic targets for prevention of muscle wasting, and vision or hearing loss.