Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.
Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.
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DOI：
10.1002/ajmg.a.62207
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Ghaloul-Gonzalez L
中科院分区：
文献类型：
--
作者：
Wolfe RM;Mohsen AW;Walsh Vockley C;Bertrand CA;Nicholls RD;Heiman P;Seibold LM;Vockley J;Ghaloul-Gonzalez L
由GUCY2C基因编码的鸟苷酸环化酶2C （GC‐C）与遗传性早发性慢性腹泻有关。几个有慢性腹泻症状的家族已被确定为常染色体显性，GUCY2C功能获得突变。我们发现了一名Mennonite患者，患有一种新的GUCY2C变异（c.2381A >t; p.Asp794Val），患有慢性腹泻，并有广泛的慢性腹泻和肠扩张的母亲家族史。包括共分离分析在内的功能研究显示，该变异的所有杂合家族成员都有GI相关症状。表达Asp794Val GC‐C变体的HEK‐293 T细胞在大肠杆菌热稳定肠毒素STp （HST）刺激下显示cGMP生成增加，而在5‐（3‐溴苯基）‐5,11‐二氢‐1,3‐二甲基‐1H‐茚二酮[2′，1′：5,6]吡啶[2,3‐d]嘧啶‐2,4,6（3H）‐三酮（BPIPP，一种GC‐C抑制剂）刺激下则相反。此外，SPQ荧光法检测的囊性纤维化跨膜传导调节因子（CFTR）活性在HST治疗后在这些细胞中升高，表明CFTR活性在这种疾病的发病机制中起着至关重要的作用。这些结果支持GC‐C Asp794Val变异的致病性是该家族慢性腹泻的一个原因。此外，这项工作确定了潜在的候选药物，GC‐C抑制剂BPIPP，用于治疗由该综合征引起的腹泻。
Guanylate cyclase 2C (GC‐C), encoded by the GUCY2C gene, is implicated in hereditary early onset chronic diarrhea. Several families with chronic diarrhea symptoms have been identified with autosomal dominant, gain‐of‐function mutations in GUCY2C. We have identified a Mennonite patient with a novel GUCY2C variant (c.2381A > T; p.Asp794Val) with chronic diarrhea and an extensive maternal family history of chronic diarrhea and bowel dilatation. Functional studies including co‐segregation analysis showed that all family members who were heterozygous for this variant had GI‐related symptoms. HEK‐293 T cells expressing the Asp794Val GC‐C variant showed increased cGMP production when stimulated with Escherichia coli heat‐stable enterotoxin STp (HST), which was reversed when 5‐(3‐Bromophenyl)‐5,11‐dihydro‐1,3‐dimethyl‐1H‐indeno[2′,1′:5,6]pyrido[2,3‐d]pyrimidine‐2,4,6(3H)‐trione (BPIPP; a GC‐C inhibitor) was used. In addition, cystic fibrosis transmembrane conductance regulator (CFTR) activity measured with SPQ fluorescence assay was increased in these cells after treatment with HST, indicating a crucial role for CFTR activity in the pathogenesis of this disorder. These results support pathogenicity of the GC‐C Asp794Val variant as a cause of chronic diarrhea in this family. Furthermore, this work identifies potential candidate drug, GC‐C inhibitor BPIPP, to treat diarrhea caused by this syndrome.
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影响因子：
24.5
作者：
Waldman SA;Camilleri M
通讯作者：
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影响因子：
29.4
作者：
Thiagarajah JR;Kamin DS;Acra S;Goldsmith JD;Roland JT;Lencer WI;Muise AM;Goldenring JR;Avitzur Y;Martín MG;PediCODE Consortium
通讯作者：
PediCODE Consortium
影响因子：
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作者：
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影响因子：
3.3
作者：
Silvis, Mark R.;Bertrand, Carol A.;Bradbury, Neil A.
通讯作者：
Bradbury, Neil A.
DOI：
10.1097/00005176-200406002-00019
发表时间：
2004-01-01
影响因子：
2.9
作者：
Bhutta, ZA;Ghishan, F;Rhoads, JM
通讯作者：
Rhoads, JM