Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk.
Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk.
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DOI：
10.1136/gutjnl-2012-303090
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发表时间：
2013-11
期刊：
影响因子：
24.5
通讯作者：
Sahin-Tóth M
中科院分区：
文献类型：
--
作者：
Beer S;Zhou J;Szabó A;Keiles S;Chandak GR;Witt H;Sahin-Tóth M
消化酶胰凝乳蛋白酶C（CTRC）通过促进胰蛋白酶原的降解从而减少潜在有害的胰蛋白酶原活化来预防胰腺炎。CTRC的功能丧失变异增加慢性胰腺炎的风险。本研究的目的是进行全面的功能分析，所有的错义CTRC的变种确定日期。我们研究了27个已发表的和5个新的CTRC突变体的分泌，活性和降解。我们还评估了5个突变体对内质网（ER）应激的影响。没有突变体表现出增加的功能，如增加分泌或活动。相反，11个突变体显示出明显的功能丧失，3个突变体有中度功能缺陷，而18个突变体的功能与野生型CTRC相似。观察到的功能缺陷是分泌减少，催化活性受损和胰蛋白酶降解。具有分泌缺陷的突变体引起与分泌损失成比例的ER应激。ER应激与催化缺陷或蛋白水解不稳定相关的功能丧失表型无关。致病性CTRC变体通过影响分泌、活性和蛋白水解稳定性的三种不同但互不排斥的机制引起功能丧失。ER应激可能由CTRC突变体的子集诱导，但不代表CTRC变体的共同病理机制。该表型数据集应有助于对慢性胰腺炎患者中鉴定的CTRC变体的临床相关性进行分类。
The digestive enzyme chymotrypsin C (CTRC) protects against pancreatitis by promoting degradation of trypsinogen and thereby curtailing potentially harmful trypsinogen activation. Loss-of-function variants in CTRC increase the risk for chronic pancreatitis. The aim of the present study was to perform comprehensive functional analysis of all missense CTRC variants identified to date. We investigated secretion, activity and degradation of 27 published and 5 novel CTRC mutants. We also assessed the effect of 5 mutants on endoplasmic reticulum (ER) stress. None of the mutants exhibited a gain of function such as increased secretion or activity. In contrast, 11 mutants showed marked loss of function, 3 mutants had moderate functional defects, whereas 18 mutants were functionally similar to wild-type CTRC. The functional deficiencies observed were diminished secretion, impaired catalytic activity and degradation by trypsin. Mutants with a secretion defect caused ER stress that was proportional to the loss in secretion. ER stress was not associated with loss-of-function phenotypes related to catalytic defect or proteolytic instability. Pathogenic CTRC variants cause loss of function by three distinct but mutually non-exclusive mechanisms that affect secretion, activity and proteolytic stability. ER stress may be induced by a subset of CTRC mutants but does not represent a common pathological mechanism of CTRC variants. This phenotypic dataset should aid in the classification of the clinical relevance of CTRC variants identified in patients with chronic pancreatitis.
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影响因子：
4.8
作者：
Szabo, Andras;Heja, David;Pal, Gabor
通讯作者：
Pal, Gabor
影响因子：
24.5
作者：
Szmola R;Sahin-Tóth M
通讯作者：
Sahin-Tóth M
DOI：
10.1111/j.1742-4658.2011.08351.x
发表时间：
2011-11
期刊：
The FEBS journal
影响因子：
--
作者：
Bence M;Sahin-Tóth M
通讯作者：
Sahin-Tóth M
影响因子：
1.8
作者：
Felderbauer, P.;Karakas, E.;Bulut, K.
通讯作者：
Bulut, K.
影响因子：
30.8
作者：
Rosendahl, Jonas;Witt, Heiko;Sahin-Toth, Miklos
通讯作者：
Sahin-Toth, Miklos