Rate of Progression of PCDH15-Related Retinal Degeneration in Usher Syndrome 1F (RUSH1F)

USH1F is a subtype of USH1 caused by bi-allelic mutations of the USH1F gene,
also called protocadherin 15 (PCDH15). It is assumed that PCDH15 might have a
role in the morphogenesis and cohesion of stereocilia bundles and retinal
photoreceptor cell maintenance or function. Protocadherin 15 deficiency leads
to functionally impaired cones and rods with abnormally shaped outer segments.
The current knowledge about the natural course of USH1F is limited, as no
systematic observational trials of the retinal phenotype have been published.
The phenotype and fast time course of the retinal degeneration in USH1F is
comparable with the phenotype of USH1 in general, which is characterized by
profound pre-lingual deafness, vestibular ataxia, and childhood onset of
retinitis pigmentosa.
Gene-based therapies such as dual-vectors, gene editing or mini genes, and
suppression of several PCDH15 mutations by aminoglycosides have been examined.
Aminoglycosides can influence the translation of mRNA into protein by
inhibiting ribosomal proofreading, thus, leading to read-through of nonsense
mutations. A partial read-through of PCDH15 nonsense mutations leading to
various levels of the full-length protein was shown by aminoglycosides in vitro
and ex vivo. However, more preclinical and clinical research is needed to
determine whether these approaches can restore vision in patients with USH1F or
slow down the degeneration process leading to blindness.

1. To report the natural history of retinal degenaration in patients with
biallelic mutations in the PCDH15 gene.
2. To identify sensitive structural and functional outcome measures to use for
future multicenter clinical trials in PCDH15-related retinal degeneration.
3. To identify well-defined subpopulations for future clinical trials of
investigative treatments for PCDH15-related retinal degeneration

This study is designed as a multicenter longitudinal, prospective natural
history study. Patients will be defined to 2 cohorts based on their visual
acuity and kinetic visual field.

We anticipate that study enrollment will be representative of the population of
patients with biallelic mutations in the PCDH15 gene.
Participants do not benefit, risks are considered negligible, procedures are
non-invasive and take 3 to 6 hours extra time from patient per visit, one visit
per year. lt is anticipated that, in the future, patients with PCDH15-related
retinal degeneration will benefit from newly developed therapeutic strategies.