Novel genotype-phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss.
LMX1A
haploinsufficiency
luciferase assay
nonsyndromic hearing loss
transcriptional factor
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
16
06
2020
revised:
10
08
2020
accepted:
19
08
2020
pubmed:
26
8
2020
medline:
11
11
2021
entrez:
26
8
2020
Statut:
ppublish
Résumé
LMX1A, encoding the LIM homeobox transcription factor, is essential for inner ear development. Despite previous reports of three human LMX1A variants with nonsyndromic hearing loss (NSHL) in the literature, functional characterization of these variants has never been performed. Encouraged by identification of a de novo, heterozygous, missense variant (c.595A > G; p.Arg199Gly) located in the homeodomain of LMX1A in a subject with congenital severe-to-profound deafness through Exome sequencing, we performed luciferase assay to evaluate transcriptional activity of all LMX1A variants reported in the literature including p.Arg199Gly. Resultantly, p.Arg199Gly manifesting the most severe NSHL showed the biggest reduction of transcriptional activity in contrast with moderately reduced activity of p.Cys97Ser and p.Val241Leu associated with less severe progressive NSHL, proposing a genotype-phenotype correlation. Further, our dominant LMX1A variant exerted pathogenic effects via haploinsufficiency rather than dominant-negative effect. Collectively, we provide a potential genotype-phenotype correlation of LMX1A variants as well as the pathogenic mechanism of LMX1A-related NSHL.
Substances chimiques
LIM-Homeodomain Proteins
0
LMX1A protein, human
0
Transcription Factors
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1877-1883Informations de copyright
© 2020 Wiley Periodicals LLC.
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