Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.
Am J Med Genet A
; 185(7): 2046-2055, 2021 07.
Article
in En
| MEDLINE
| ID: mdl-33949097
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cystic Fibrosis Transmembrane Conductance Regulator
/
Genetic Predisposition to Disease
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Diarrhea
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Receptors, Enterotoxin
Type of study:
Prognostic_studies
Limits:
Adolescent
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Adult
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Child
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Female
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Humans
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Male
Language:
En
Journal:
Am J Med Genet A
Journal subject:
GENETICA MEDICA
Year:
2021
Document type:
Article
Affiliation country: