Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea.
Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea.
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先天性吸收性腹泻婴儿PCSK1基因的新型纯合失活突变。
DOI：
10.3390/genes12050710
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发表时间：
2021-05-10
期刊：
影响因子：
3.5
通讯作者：
Creemers JW
中科院分区：
文献类型：
--
作者：
Aerts L;Terry NA;Sainath NN;Torres C;Martín MG;Ramos-Molina B;Creemers JW
前蛋白转化酶1/3（PC 1/3），由PCSK 1基因编码，在神经元和（肠）内分泌细胞类型中表达，在那里它切割并因此激活许多在能量稳态中起关键作用的蛋白质前体。PCSK 1的功能缺失突变导致以吸收不良性腹泻和早发性肥胖为特征的隐性复杂内分泌病。尽管事实上，新生儿吸收不良性腹泻是观察到所有的患者，它仍然是研究不足。本研究的目的是调查肠内分泌病理的男性患者先天性PCSK 1缺陷携带新的纯合子c.1034A>C（p.E345A）突变。该患者在出生后第一周内出现吸收不良性腹泻和代谢性酸中毒，但在全胃肠外营养后观察到体重迅速增加，并显示高胰岛素原水平和低促肾上腺皮质激素水平。体外分析表明，PC 1/3中的p.E345A突变导致（接近）正常的自催化proPC 1/3加工，仅部分损害PC 1/3分泌，但反式底物的加工被完全阻断。免疫组织化学染色未显示结肠组织中proGIP/GIP和胰高血糖素原/GLP-1比值的变化。因此，我们报告了一个新的PCSK 1缺乏症的病人，尽管新生儿吸收不良性腹泻，表现出正常的小肠形态。
Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in PCSK1 cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital PCSK1 deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.
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影响因子：
2.6
作者：
Mace OJ;Tehan B;Marshall F
通讯作者：
Marshall F
影响因子：
29.4
作者：
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通讯作者：
PediCODE Consortium
影响因子：
29.4
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通讯作者：
Georgia S
影响因子：
158.5
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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