Molecular Genetic Characterization of Alstrom Syndrome

本研究的目的是确定Alstrom综合征的分子基础，Alstrom综合征是一种隐性疾病，其特征是在普通人群中经常观察到的条件。 这些包括在他们的第二至第四个十年的生活中进行性听力和视网膜功能不全。我们本地化的Alstrom基因，ALMS 1，到Chr.2p13的纯合性映射在一个大的法国人的亲属和零星的家庭连锁分析。 目前，含有ALMS 1的最小区域的大小小于1 cM，跨越0.6-0.8 Mb的基因组DNA。该建议的具体目标包括：1）鉴定导致Alstrom综合征的突变转录物以及ALMS 1基因内突变的谱和频率。 我们将继续缩小Alstrom关键区域，并通过分析该区域中所有可用的序列来完成其中包含的序列的组装和注释，通过直接测序该区域内的转录本来识别ALMS 1基因，以检测突变并将其与疾病表型相关联。(2)开发小鼠模型以研究Alstrom病病理学和进展。 更具体地说，我们将确定Alms 1基因的时间和空间表达模式，生成Alms 1基因的无效突变体，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遗传修饰剂。在这个建议的成功结论，我们将确定Alstrom基因，并产生一个动物模型，允许进一步研究的病因和病理的突变Alms 1等位基因。 耳聋、失明和肥胖的特征已经在许多儿童综合征中描述，表明共同发育途径中的基本缺陷。 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。 对基因产物、其表达模式以及它如何影响其他基因的研究将有助于更好地了解正常生物途径的功能。 此外，我们认为，Alstrom基因的鉴定可能提供了一种新的代谢和调控途径，这些途径参与了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.