Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis
Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis
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DOI：
10.1016/j.ymgme.2007.06.006
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发表时间：
2007-09-01
影响因子：
3.8
通讯作者：
Ferec, Claude
中科院分区：
文献类型：
--
作者：
Masson, Emmanuelle;Le Marechal, Cedric;Ferec, Claude
为了快速高效地分析胰腺分泌型胰蛋白酶抑制剂（SPINK1）基因的突变，建立了定量荧光多重PCR （qfp -PCR）方法。使用qfp - pcr，在9个新招募的慢性胰腺炎法国高加索家族中发现了一个包含整个SPINK1基因的新型杂合缺失。断点被充分表征，与30 kb缺失相似的断点被命名为c.1-15969 c.240+7702del30588bp。虽然有可能形成非b DNA结构的序列被发现跨越5‘和3’缺失断点，但这种严重缺失的产生可能是由于两端存在1 bp的微同源性，从而促进了非同源末端连接。在该患者中发现的SPINK1基因缺失也在其患病父亲和父亲叔叔中检测到，但在50名健康的法国白种人中未检测到。值得注意的是，在所有三个受影响的个体中，SPINK1缺失被发现与非连锁CFTR基因的杂合p.L997F错义突变共同遗传，这种病变先前报道与多种囊性纤维化相关疾病包括特发性胰腺炎相关。鉴于SPINK1缺失是一个明确的致病因素，CFTR错义突变可能在这个特定家族中起着疾病修饰因子的作用。(C) 2007爱思唯尔公司版权所有。
Quantitative fluorescent multiplex PCR (QFM-PCR) was established in order to make possible the rapid and efficient mutational analysis of the pancreatic secretory trypsin inhibitor (SPINK1) gene. Using QFM-PCR, a novel heterozygous deletion encompassing the entire SPINK1 gene was identified in one of nine newly recruited French Caucasian families with chronic pancreatitis. The breakpoints were fully characterized and the similar to 30 kb deletion was termed c.1-15969 c.240+7702del30588bp. Whilst sequences with the potential to form non-B DNA structures were found to span both the 5' and 3' deletion breakpoints, the generation of this gross deletion is potentially explicable in terms of non-homologous end-joining facilitated by the presence of a 1-bp microhomology at the two ends. The SPINK1 gene deletion identified in the index patient was also detected in her affected father and paternal uncle but not in 50 healthy French Caucasians. Remarkably, in all three affected individuals, the SPINK1 deletion was found to be co-inherited with a heterozygous p.L997F missense mutation in the unlinked CFTR gene, a lesion previously reported to be associated with a variety of cystic fibrosis-related diseases including idiopathic pancreatitis. Given that the SPINK1 deletion constitutes a clear-cut disease-causing factor, it may be that the CFTR missense mutation acts as a disease modifier in the context of this particular family. (C) 2007 Elsevier Inc. All rights reserved.