Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Genet Med. 2010 Sep;12(9):548-55. doi: 10.1097/GIM.0b013e3181ead634.
To evaluate the role of complex alleles, with two or more mutations in cis position, of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the definition of the genotype-phenotype relationship in cystic fibrosis (CF), and to evaluate the functional significance of the highly controversial L997F CFTR mutation.
We evaluated the diagnosis of CF or CFTR-related disorders in 12 unrelated subjects with highly variable phenotypes. According to a first CFTR mutational analysis, subjects appeared to be compound heterozygotes for a classic mutation and the L997F mutation. A further CFTR mutational analysis was conducted by means of a protocol of extended sequencing, particularly suited to the detection of complex alleles.
We detected a new [R117L; L997F] CFTR complex allele in the four subjects with the highest sweat test values and CF. The eight subjects without the complex allele showed the most varied biochemical and clinical outcome and were diagnosed as having mild CF, CFTR-related disorders, or even no disease.
The new complex allele partially explains the variable phenotype in CF subjects with the L997F mutation. CFTR complex alleles are likely to have a role in the definition of the genotype-phenotype relationship in CF. Whenever apparently identical CFTR-mutated genotypes are found in subjects with divergent phenotypes, an extensive mutational search is mandatory.
评估囊性纤维化跨膜电导调节因子 (CFTR) 基因中两个或多个顺式位置突变的复杂等位基因在囊性纤维化 (CF) 基因型-表型关系定义中的作用，并评估备受争议的 L997F CFTR 突变的功能意义。
我们评估了 12 名表型高度可变的无关联个体中 CF 或 CFTR 相关疾病的诊断。根据首次 CFTR 突变分析，这些个体似乎是经典突变和 L997F 突变的复合杂合子。通过扩展测序方案进行了进一步的 CFTR 突变分析，该方案特别适合检测复杂等位基因。
我们在四个汗液测试值最高且患有 CF 的个体中检测到一种新的 [R117L; L997F] CFTR 复合等位基因。没有复杂等位基因的八个个体表现出最具差异的生化和临床结果，被诊断为患有轻度 CF、CFTR 相关疾病，甚至没有疾病。
新的复合等位基因部分解释了具有 L997F 突变的 CF 个体的可变表型。CFTR 复杂等位基因可能在 CF 基因型-表型关系的定义中发挥作用。无论在表型不同的个体中发现明显相同的 CFTR 突变基因型，都需要进行广泛的突变搜索。
