Two rare variants reveal the significance of Grainyhead-like 3 Arginine 391 underlying non-syndromic cleft palate only.
Oral Dis
; 29(4): 1632-1643, 2023 May.
Article
en En
| MEDLINE
| ID: mdl-35189007
ABSTRACT
OBJECTIVES:
Non-syndromic cleft palate only (NSCPO) is one of the most common craniofacial birth defects with largely undetermined genetic etiology. It has been established that Grainyhead-like 3 (GRHL3) plays an essential role in the pathogenesis of NSCPO. This study aimed to identify and verify the first-reported GRHL3 variant underlying NSCPO among the Chinese cohort.METHODS:
We performed whole-exome sequencing (WES) on a Chinese NSCPO patient and identified a rare variant of GRHL3 (p.Arg391His). A validated deleterious variant p.Arg391Cys was introduced as a positive control. Zebrafish embryos injection, reporter assays, live-cell imaging, and RNA sequencing were conducted to test the pathogenicity of the variants.RESULTS:
Zebrafish embryos microinjection demonstrated that overexpression of the variants could disrupt the normal development of zebrafish embryos. Reporter assays showed that Arg391His disturbed transcriptional activity of GRHL3 and exerted a dominant-negative effect. Interestingly, Arg391His and Arg391Cys displayed distinct nuclear localization patterns from that of wild-type GRHL3 in live-cell imaging. Bulk RNA sequencing suggested that the two variants changed the pattern of gene expression.CONCLUSIONS:
In aggregate, this study identified and characterized a rare GRHL3 variant in NSCPO, revealing the critical role of Arginine 391 in GRHL3. Our findings will help facilitate understanding and genetic counseling of NSCPO.Palabras clave
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Banco de datos:
MEDLINE
Asunto principal:
Labio Leporino
/
Fisura del Paladar
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2023
Tipo del documento:
Article