Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden.
Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden.
复制标题
转甲状腺素蛋白基因内部和周围的单倍型和 DNA 序列变异：葡萄牙和瑞典家族性淀粉样多发性神经病 (V30M) 的基因型-表型相关性。
DOI：
10.1038/sj.ejhg.5201095
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Buxbaum,JoelN
中科院分区：
文献类型：
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作者：
Soares,MiguelLuz;Coelho,Teresa;Sousa,Alda;Holmgren,Gosta;Saraiva,MariaJoao;Kastner,DanielL;Buxbaum,JoelN
家族性淀粉样多发性神经病(FAP)是一种致死性常染色体显性遗传性疾病，由甲状腺激素(T4)和视黄醇结合蛋白(视黄醇结合蛋白)的正常血浆载体转甲状腺蛋白(TTR)的突变形式产生的纤维沉积在组织中。超过80个TTR序列变异与FAP相关，但仅靠氨基酸替换并不能完全解释疾病外显性、病理学和临床病程的差异。为了分析可能导致这种表型变异的因素，我们通过对葡萄牙和瑞典V30M携带者的基因组DNA进行扩展微卫星单倍型分析、测序和单核苷酸多态单倍型分析，表征了野生型和突变型(Val30Met)TTR基因及其侧翼序列的变异。我们在TTR非翻译区发现了10个新的多态，其中8个是由单碱基替换引起的，2个是由二核苷酸重复序列的插入/缺失引起的。这些数据表明，FAP V30M的症状可能是由伴随的非携带者染色体(由微卫星D18S457和D18S456定义)上TTR下游的一个间隔所调控的，而不是由TTR5‘和3’侧翼序列所调控的。在这些研究过程中，我们还遇到了第一个例子，在葡萄牙人群中，前面描述的单倍型III可能与V30M FAP有关。
Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T 4) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5′-and 3′-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population.