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，其特征是在一般人群中经常观察到的情况。这些包括在他们生命的第二到第四十年进行性听力和视网膜功能不全。我们通过在一个法国阿卡迪亚大型亲属中进行纯合定位，并通过对散发性家庭的连锁分析，将ALMS1基因定位在Chr. 2p13上。目前，包含ALMS1的最小区域的大小小于1 cM，跨越0.6-0.8 Mb的基因组DNA。本提案的具体目的包括：1)鉴定导致Alstrom综合征的突变转录本以及ALMS1基因内突变的频谱和频率。我们将继续缩小Alstrom临界区域，并通过分析该区域所有可用的序列，完成其中包含的序列的组装和注释，通过对该区域内转录本的直接测序来识别ALMS1基因，以检测突变并将其与疾病表型相关联。(2)建立小鼠模型以研究Alstrom病的病理和进展。更具体地说，我们将确定Alms1基因的时空表达模式，生成Alms1基因的零突变体，并评估该模型对人类疾病的忠实程度。我们还将测试在Alstrom综合征中观察到的表型变异是否可能是由于基因修饰。在这一建议的成功结论，我们将已经确定了Alstrom基因，并产生了一个动物模型，允许进一步研究突变Alms1等位基因的病因和病理。耳聋、失明和肥胖的特征在许多儿童综合症中都有描述，这表明在共同的发育途径中存在基本缺陷。定位和识别导致阿尔斯特罗姆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。对该基因产物、其表达模式及其对其他基因的影响的研究将有助于更好地了解正常生物途径的功能。此外，我们相信Alstrom基因的鉴定可能为上述常见复杂疾病特征和相关疾病的病因学提供新的代谢和调节途径。

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.