Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F

Area of Science:

• Genetics
• Ophthalmology
• Audiology

Background:

• Usher syndrome type 1F (USH1F) is a genetic disorder characterized by congenital hearing loss and progressive vision impairment.
• The genetic locus for USH1F was previously mapped, but the causative gene remained unidentified.

Purpose of the Study:

• To determine the molecular basis of Usher syndrome type 1F (USH1F).
• To identify the gene responsible for USH1F and elucidate its role in retinal and cochlear function.

Main Methods:

• Fluorescence in situ hybridization (FISH) to localize the human PCDH15 gene.
• Genomic sequencing to identify mutations in the PCDH15 gene in affected families.
• Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry to assess PCDH15 expression in retinal and cochlear tissues.

Main Results:

• The human homolog of mouse Pcdh15 was localized to the USH1F linkage interval.
• Two distinct mutations in the PCDH15 gene (a single-base deletion and a nonsense mutation) were identified in two families with USH1F.
• PCDH15 expression was confirmed in the retina and cochlea, consistent with the observed phenotypes.

Conclusions:

• Mutations in the PCDH15 gene are the molecular cause of Usher syndrome type 1F.
• PCDH15 is essential for the normal function of both the retina and the cochlea.
• This finding expands the role of protocadherins in sensory organ development and maintenance.