Loss-of-function variants in KLF4 underlie autosomal dominant palmoplantar keratoderma.
Genet Med
; 24(5): 1085-1095, 2022 05.
Article
em En
| MEDLINE
| ID: mdl-35168889
ABSTRACT
PURPOSE:
Palmoplantar keratodermas (PPKs) form a group of disorders characterized by thickening of palm and sole skin. Over the past 2 decades, many types of inherited PPKs have been found to result from abnormal expression, processing, or function of adhesion proteins.METHODS:
We used exome and direct sequencing to detect causative pathogenic variants. Functional analysis of these variants was conducted using reverse transcription quantitative polymerase chain reaction, immunofluorescence confocal microscopy, immunoblotting, a promoter reporter assay, and chromatin immunoprecipitation.RESULTS:
We identified 2 heterozygous variants (c.1226A>G and c.633_634dupGT) in KLF4 in 3 individuals from 2 different unrelated families affected by a dominant form of PPK. Immunofluorescence staining for a number of functional markers revealed reduced epidermal DSG1 expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or downregulated for KLF4 displayed reduced DSG1 expression, which in turn has previously been found to be associated with PPK. A chromatin immunoprecipitation assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to transactivate the DSG1 promoter was significantly decreased when compared with wild-type KLF4.CONCLUSION:
Loss-of-function variants in KLF4 cause a novel form of dominant PPK and show its importance in the regulation of epidermal differentiation.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ceratodermia Palmar e Plantar
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Genet Med
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Israel