Genotype-phenotype correlation in cystic fibrosis: The role of modifier genes
Genotype-phenotype correlation in cystic fibrosis: The role of modifier genes
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DOI：
10.1002/ajmg.10461
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发表时间：
2002-07-22
期刊：
影响因子：
--
通讯作者：
Castaldo, G
中科院分区：
文献类型：
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作者：
Salvatore, F;Scudiero, O;Castaldo, G
在囊性纤维化（CF）跨膜调节因子（CFTR）疾病基因中已发现超过1，000种突变。这些突变对蛋白质的影响和广泛的CF表型促使了一系列基因型-表型相关性研究。CFTR基因型总是与胰腺状态相关，约85%的胰腺功能不全病例和约150%的胰腺功能不全病例中CFTR基因型与胰腺状态相关。CFTR基因型与肺、肝和胃肠道表达之间的相关性是有争议的。携带相同基因型或无义突变纯合子的CF患者的异质表型涉及疾病中的环境和/或遗传因素。然而，CF兄弟姐妹中观察到的不一致表型反对环境因素的主要作用，并建议CFTR以外的基因调节CF表型。在小鼠中以及随后在人类中鉴定了调节胃肠道表达的基因座。通过分析9例与胎粪性肠梗阻不一致的CF患者，我们能够表明该位点具有显性效应。此外，在一项合作研究中，我们发现CF患者和对照组中β-防御素基因1和2的多态性率较高。在另一项多中心研究中，发现α-1抗胰蛋白酶（A1 AT）和甘露糖结合凝集素基因突变是CF患者肝脏疾病的独立风险因素。现有的证据表明，杂色CF表型的结果从许多基因产物之间的复杂的相互作用。(C)2002 Wiley-Liss，Inc.
More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype-Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status-in about 85% of cases with pancreatic insufficiency and in about 150 of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in beta-defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in alpha-1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products. (C) 2002 Wiley-Liss, Inc.