Masson Emmanuelle, Le Maréchal Cédric, Chandak Giriraj R, Lamoril Jérôme, Bezieau Stephane, Mahurkar Swapna, Bhaskar Seema, Reddy D Nageshwar, Chen Jian-Min, Férec Claude
Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France.
Clin Gastroenterol Hepatol. 2008 Jan;6(1):82-8. doi: 10.1016/j.cgh.2007.10.004. Epub 2007 Dec 11.
BACKGROUND & AIMS: We have recently reported that the triplication of a approximately 605 kilobase segment containing the PRSS1 (encoding cationic trypsinogen) and PRSS2 (encoding anionic trypsinogen) genes causes hereditary pancreatitis. Here we went further to investigate whether this copy number mutation could account for some unidentified French white patients with idiopathic chronic pancreatitis (ICP) or familial chronic pancreatitis (FCP) as well as Indian patients with tropical calcific pancreatitis (TCP).
Patients and controls were screened by means of previously described quantitative fluorescent multiplex polymerase chain reaction and/or genotyping of the microsatellite marker rs3222967.
The approximately 605 kilobase triplication and a novel duplication (confirmed by fluorescence in situ hybridization) of the trypsinogen locus were detected in 10 and 2 of 202 ICP patients, respectively (age of disease onset, <or=20 years) but were absent in 282 French controls. In addition, the duplication mutation was found in 2 of 1044 ICP patients whose age of disease onset was >20 years. However, the 2 trypsinogen copy number mutations were observed in neither 103 FCP patients nor 268 Indian TCP patients.
Our findings revealed the molecular basis of 6% of the young ICP patients and further demonstrated that chronic pancreatitis is a genomic disorder. Our findings also add to the mounting evidence showing that trypsinogen gene mutations do not appear to play an important role in the pathogenesis of TCP in the Indian population. Finally, a dividend of this study is that we have provided convincing evidence to show that all 5 previously described copy number variations involving PRSS1 or/and PRSS2 are artifacts.
我们最近报道，包含PRSS1（编码阳离子胰蛋白酶原）和PRSS2（编码阴离子胰蛋白酶原）基因的一个约605千碱基片段的三倍体导致遗传性胰腺炎。在此，我们进一步研究这种拷贝数突变是否可解释一些不明原因的法国特发性慢性胰腺炎（ICP）或家族性慢性胰腺炎（FCP）白人患者以及印度热带钙化性胰腺炎（TCP）患者的病因。
通过先前描述的定量荧光多重聚合酶链反应和/或微卫星标记rs3222967的基因分型对患者和对照进行筛查。
在202例ICP患者（发病年龄≤20岁）中，分别有10例和2例检测到胰蛋白酶原基因座的约605千碱基三倍体和一种新的重复（经荧光原位杂交证实），但在282名法国对照中未检测到。此外，在1044例发病年龄>20岁的ICP患者中有2例发现了重复突变。然而，在103例FCP患者和268例印度TCP患者中均未观察到这两种胰蛋白酶原拷贝数突变。
我们的研究结果揭示了6%的年轻ICP患者的分子基础，并进一步证明慢性胰腺炎是一种基因组疾病。我们的研究结果还进一步证明，胰蛋白酶原基因突变似乎在印度人群TCP的发病机制中不起重要作用。最后，本研究的一个收获是，我们提供了令人信服的证据表明，先前描述的涉及PRSS1或/和PRSS2的所有5种拷贝数变异都是人为因素造成的。
