Molecular Genetics of Muscular/Neurosensory Models

描述(由申请人提供)：我们最近发现了一个自发的 小鼠突变，面纱(Vis)，有视网膜血管病变，听力损失和进行性肌肉萎缩，许多人类疾病的表型报道，如 如Coat病、综合征性和非综合征性先天性耳聋，以及 分别为肌营养不良症。我们已经将面纱映射到0.19+/-0.13厘米 鼠标频率的间隔。8在1,072个减数分裂重组杂交组合中建立 临界区的物理重叠群。人类胆汁的一部分。2、4Q、8、 13、17、18、19和22映射到该区域，其断点尚未 要精致。有趣的是，面纱具有许多(如果不是全部)表型 据报道患有筋膜肩周性肌营养不良症(FSHD)， 第三种最常见的肌营养不良症，影响1/20,000人，并与人类 Cr.4q35。此外，与高度可变的发病年龄相关的神经肌病 映射到Chr.19pl3。面纱是一种潜在的遗传和/或表型模型 这些疾病。面纱鼠标也是独一无二的，因为它显示视网膜 分层异常，一种以前没有报道过的表型 文学作品。 为了了解这种疾病背后的生物学机制 过程，并确定在不同的过程中影响的生化途径 组织，我们将：(A)定位克隆面纱基因并鉴定 第二个等位基因myd的突变，并检验表型 用等位基因异质性来解释v/S和myd的差异； 开始识别遗传背景中可以显著改变的基因 VIS/VIS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。 对致病基因和动物模型的识别是非常重要的 很重要。人类的许多疾病，特别是那些涉及眼睛的疾病，如果 及早发现，可以治疗，以减轻疾病的进程。如果没有 在了解这种疾病的分子基础后，目前可以进行治疗 可能会为新的治疗方案提供见解，然后这些模型就可以使用 来测试这些疗法。最后，对致病基因的了解可能 导致对维持正常的关键途径的理解 生物体的功能和生理学，也许，可以识别治疗 预防肌肉萎缩和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.