Syntaxin 4 is essential for hearing in human and zebrafish.

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• Congenital hearing impairment (HI) is a complex genetic disorder requiring early diagnosis.
• Genetic heterogeneity complicates the identification of causative genes for HI.

Purpose of the Study:

• Investigate the genetic basis of severe-to-profound HI in a consanguineous Pakistani family.
• Identify the specific gene and mutation responsible for HI in the affected individuals.

Main Methods:

• Exome sequencing was performed on a large consanguineous family with multiple affected individuals.
• Segregation analysis and LOD score calculation were used to confirm the association of the variant with HI.
• In silico analysis, immunofluorescence, and zebrafish knockdown models were employed to study gene function.

Main Results:

• A homozygous splice region variant (c.232+6T>C) in the STX4 gene was identified and segregated with HI.
• STX4 is highly expressed in the developing and adult inner ear, localizing to hair cells.
• Zebrafish knockdown of STX4 resulted in abnormal startle responses and disrupted hair cell mechanotransduction.

Conclusions:

• STX4 dysfunction is a novel cause of congenital hearing impairment in humans.
• The findings underscore the conserved role of STX4 in inner ear development and hair cell function across species.
• This research expands the genetic landscape of hearing loss and provides insights into molecular mechanisms.