Null mutations of NEUROG3 are associated with delayed-onset diabetes mellitus.
JCI Insight
; 5(1)2020 01 16.
Article
en En
| MEDLINE
| ID: mdl-31805014
ABSTRACT
Biallelic mutations of the gene encoding the transcription factor NEUROG3 are associated with a rare disorder that presents in neonates as generalized malabsorption - due to a complete absence of enteroendocrine cells - followed, in early childhood or beyond, by insulin-dependent diabetes mellitus (IDDM). The commonly delayed onset of IDDM suggests a differential requirement for NEUROG3 in endocrine cell generation in the human pancreas versus the intestine. However, previously identified human mutations were hypomorphic and, hence, may have had residual function in pancreas. We report 2 patients with biallelic functionally null variants of the NEUROG3 gene who nonetheless did not present with IDDM during infancy but instead developed permanent IDDM during middle childhood ages. The variants showed no evidence of function in traditional promoter-based assays of NEUROG3 function and also failed to exhibit function in a variety of potentially novel in vitro and in vivo molecular assays designed to discern residual NEUROG3 function. These findings imply that, unlike in mice, pancreatic endocrine cell generation in humans is not entirely dependent on NEUROG3 expression and, hence, suggest the presence of unidentified redundant in vivo pathways in human pancreas capable of yielding ß cell mass sufficient to maintain euglycemia until early childhood.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Predisposición Genética a la Enfermedad
/
Diabetes Mellitus
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
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Mutación con Pérdida de Función
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Proteínas del Tejido Nervioso
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Child
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Female
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Humans
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Male
Idioma:
En
Revista:
JCI Insight
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos