Molecular Genetic Characterization of Alstrom Syndrome

这项研究的目的是确定阿尔斯特罗姆综合征的分子基础，这是一种隐性疾病，其特征是在普通人群中经常观察到的疾病。这些包括进行性听力和视网膜功能不全在他们生命的第二到第四个十年。我们将Alstrom基因ALMS1定位于Chr.2p13基因在一个法国阿卡迪亚人大家系中的纯合子作图和散发性家系的连锁分析。目前，含有ALMS1的最小区域不到1厘米，跨越0.6-0.8Mb的基因组DNA。这项建议的具体目标包括：1)鉴定导致阿尔斯特罗姆综合征的突变转录本，以及ALMS1基因突变的光谱和频率。我们将继续缩小Alstrom关键区的范围，并通过分析该区域的所有可用序列来完成其中包含的序列的组装和注释，通过直接对区域内的转录本进行测序来识别ALMS1基因，以检测突变并将其与疾病表型相关联。(2)为了研究Alstrom病的病理和进展，建立了小鼠模型。更具体地说，我们将确定Alms1基因的时间和空间表达模式，产生Alms1基因的零突变，并评估该模型对人类疾病的忠诚度。我们还将测试在Alstrom综合征中观察到的表型可变性是否可能是由于遗传修饰因素造成的。在这项提议的成功结束时，我们将识别出Alstrom基因并生成一个动物模型，以便对突变的Alms1等位基因的病因学和病理学进行深入研究。耳聋、失明和肥胖的特征在许多儿童综合征中都有描述，这表明常见发育途径存在基本缺陷。定位和识别导致Alstrom的基因和分子缺陷可能会让我们深入了解这些途径是什么。研究基因产物、其表达模式以及它对其他基因的影响将有助于更好地理解正常的生物途径是如何发挥作用的。此外，我们认为，Alstrom基因的鉴定可能会提供新的代谢和调控途径，涉及上述常见复杂疾病特征和相关疾病的病因学。

The objective of this research is to determine the molecular basis of Alstrom Syndrome, a recessive disease characterized by conditions that are frequently observed in the general population. These include progressive aural and retinal insufficiency in their 2nd to 4th decade of life. We localized the Alstrom gene, ALMS1, to Chr. 2p13 by homozygosity mapping in a large French Acadian kindred and by linkage analysis of sporadic families. Currently, the minimal region containing the ALMS1 is less than 1 cM in size and spans 0.6-0.8 Mb of genomic DNA. The specific aims of this proposal include: 1) Identification of the mutant transcript responsible for Alstrom Syndrome and of the spectrum and frequency of mutations within the ALMS1 gene. We will continue to narrow the Alstrom critical region and complete the assembly and annotation of the sequences contained within it by analyzing all of the available sequences in this region, to identify the ALMS1 gene by direct sequencing of transcripts within the region to detect mutations and correlate them to disease phenotypes. (2) Development of a mouse model in order to study Alstrom disease pathology and progression. More specifically, we will identify the temporal and spatial expression pattern of the Alms1 gene, generate a null mutant of the Alms1 gene and evaluate how faithful the model is to the human disease. We will also test whether the phenotypic variability observed in Alstrom Syndrome may be due to genetic modifiers. At the successful conclusion of this proposal, we will have identified the Alstrom gene and generated an animal model to allow for advanced studies of the etiology and pathology of a mutant Alms1 allele. The characteristics of deafness, blindness and obesity have been described in a number of childhood syndromes, suggesting a basic defect in common developmental pathways. Locating and identifying the gene and the molecular defect causing Alstrom may give us insight into what those pathways are. Study of the gene product, its pattern of expression and how it impacts on other genes will lead to better understanding of how normal biological pathways function. In addition, we believe that the identification of the Alstrom gene may provide access to novel metabolic and regulatory pathways involved in the etiology of common complex disease traits described above and related disorders.