Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alstrom syndrome
Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alstrom syndrome
复制标题
DOI：
10.1002/humu.20577
复制
发表时间：
2007-11-01
期刊：
影响因子：
3.9
通讯作者：
Naggert, Juergen K.
中科院分区：
文献类型：
--
作者：
Marshall, Jan D.;Hinman, Elizabeth G.;Naggert, Juergen K.
Alstrom 综合征是一种单基因隐性遗传病，具有一系列临床表现，伴有系统性纤维化和多器官受累，包括视网膜变性、听力损失、儿童肥胖、糖尿病、扩张型心肌病 (I)CM)、泌尿功能障碍以及肺、肝和肾功能衰竭。我们评估了一大群阿尔斯特罗姆综合征患者的 ALMS1 基因突变情况。总共鉴定出 79 个致病变异，其中 55 个是新突变。尽管我们还在外显子 12 和 18 中发现了新的突变，但这些变体主要聚集在外显子 8、10 和 16 中。大多数等位基因仅被识别一次 (45/79)，但有几个等位基因会反复被发现。英国和土耳其血统的家庭可能会受到创始人效应的影响。我们还鉴定了 66 个 SNP，并根据蛋白质的保守性和由此产生的氨基酸取代的严重性评估了这些变体的功能意义。一项基因型-表型关联研究检查了 58 名患者的 18 个表型参数，发现外显子 16 的致病变异与 1 岁前视网膜变性（P = 0.02）、泌尿功能障碍（P = 0.02）、DCM（P = 0.03）和糖尿病（P = 0.03）的发生之间存在提示性关联。外显子 8 的改变与无肾病、轻度肾病或迟发性肾病之间存在显着相关性 (P = 0.0007)。该数据可能对理解 ALMS1 的分子机制具有重要意义，并为进一步研究 ALMS1 的选择性剪接如何导致疾病的严重程度提供了基础。
Alstrom syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (I)CM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alstrom syndrome for mutations in the ALMS1 gene. In total, 79 disease,causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease.