Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.
Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.
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DOI：
10.1053/j.gastro.2013.03.048
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发表时间：
2013-07
期刊：
影响因子：
29.4
通讯作者：
Georgia S
中科院分区：
文献类型：
--
作者：
Martín MG;Lindberg I;Solorzano-Vargas RS;Wang J;Avitzur Y;Bandsma R;Sokollik C;Lawrence S;Pickett LA;Chen Z;Egritas O;Dalgic B;Albornoz V;de Ridder L;Hulst J;Gok F;Aydoğan A;Al-Hussaini A;Gok DE;Yourshaw M;Wu SV;Cortina G;Stanford S;Georgia S
前蛋白转化酶1/3（PC 1/3）缺乏症是一种由PCSK 1基因罕见突变引起的常染色体隐性遗传疾病，与肥胖、严重吸收不良性腹泻和某些内分泌异常相关。在几项人群研究中，PCSK 1的常见变异也与杂合子肥胖相关。PC 1/3是一种内切蛋白酶，可加工内分泌和神经细胞中表达的多种激素原。我们研究了PC 1/3缺陷症的临床和分子特征。我们研究了1/3例PC 1/3缺陷症患儿的临床特征，并进行了PCSK 1基因的序列分析。我们测量了重组PC 1/3蛋白的酶活性。我们确定了一种以年龄依赖性方式发展的内分泌疾病模式。其中8个突变在体外具有严重的生化后果。新生儿有严重的吸收不良性腹泻和发育不良，需要长期的肠外营养支持，死亡率高。随着疾病的进展，其他内分泌异常也会发生，包括尿崩症、生长激素缺乏症、原发性性腺功能减退症、肾上腺功能不全和甲状腺功能减退症。我们确定生长激素缺乏、中枢性尿崩症和男性性腺功能减退是PCSK 1不足的新特征。有趣的是，尽管早期生长异常，中度肥胖，与严重的多食，通常出现。在一项对1/3名因PCSK 1破坏而导致PC 1/3缺乏症的儿童进行的研究中，肠内分泌细胞无法产生功能性激素导致全身吸收不良。这些发现表明，PC 1/3参与处理营养吸收所需的一种或多种肠道激素。
Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal recessive disorder caused by rare mutations in the PCSK1 gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 have also been associated with obesity in heterozygotes in several population studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in processing of one or more enteric hormones that are required for nutrient absorption.
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影响因子：
15.9
作者：
Sanchez, VC;Goldstein, J;Nillni, EA
通讯作者：
Nillni, EA
影响因子：
158.5
作者：
Wang, Jiafang;Cortina, Galen;Martin, Martin G.
通讯作者：
Martin, Martin G.
影响因子：
30.8
作者：
Benzinou, Michael;Creemers, John W. M.;Froguel, Philippe
通讯作者：
Froguel, Philippe
影响因子：
7.7
作者：
Creemers JW;Choquet H;Stijnen P;Vatin V;Pigeyre M;Beckers S;Meulemans S;Than ME;Yengo L;Tauber M;Balkau B;Elliott P;Jarvelin MR;Van Hul W;Van Gaal L;Horber F;Pattou F;Froguel P;Meyre D
通讯作者：
Meyre D
影响因子：
4.8
作者：
Zhu, Xiaorong;Cao, Yun;Steiner, Donald F.
通讯作者：
Steiner, Donald F.