Genetic variants and altered expression of SERPINF1 confer disease susceptibility in patients with otosclerosis.
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Sep 2023
Sep 2023
Historique:
received:
15
12
2022
accepted:
27
04
2023
revised:
27
03
2023
medline:
28
8
2023
pubmed:
13
6
2023
entrez:
12
6
2023
Statut:
ppublish
Résumé
Otosclerosis (OTSC) is a focal and diffuse bone disorder of the human middle ear characterized by abnormal bone growth and deposition at the stapes' footplate. This hinders the transmission of acoustic waves to the inner ear leading to subsequent conductive hearing loss. The plausible convections for the disease are genetic and environmental factors with yet an unraveled root cause. Recently, exome sequencing of European individuals with OTSC revealed rare pathogenic variants in the Serpin Peptidase Inhibitor, Clade F (SERPINF1) gene. Here, we sought to investigate the causal variants of SERPINF1 in the Indian population. The gene and protein expression was also evaluated in otosclerotic stapes to ameliorate our understanding of the potential effect of this gene in OTSC. A total of 230 OTSC patients and 230 healthy controls were genotyped by single-strand conformational polymorphism and Sanger sequencing methods. By comparing the case controls, we identified five rare variants (c.72 C > T, c.151 G > A, c.242 C > G, c.823 A > T, and c.826 T > A) only in patients. Four variants c.390 T > C (p = 0.048), c.440-39 C > T (p = 0.007), c.643 + 9 G > A (p = 0.035), and c.643 + 82 T > C (p = 0.005) were found to be significantly associated with the disease. Down-regulation of SERPINF1 transcript level in otosclerotic stapes was quantified by qRT-PCR, ddPCR and further validated by in situ hybridization. Similarly, reduced protein expression was observed by immunohistochemistry and immunofluorescence in otosclerotic stapes that corroborate with immunoblotting of patients' plasma samples. Our findings identified that SERPINF1 variants are associated with the disease. Furthermore, reduced expression of SERPINF1 in otosclerotic stapes might contribute to OTSC pathophysiology.
Identifiants
pubmed: 37308566
doi: 10.1038/s10038-023-01158-w
pii: 10.1038/s10038-023-01158-w
doi:
Substances chimiques
pigment epithelium-derived factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
635-642Subventions
Organisme : Department of Science and Technology, Ministry of Science and Technology (DST)
ID : DST/INT/TUNISIA/P-19/2017
Informations de copyright
© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.
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