Project: Research project

Project Details


DESCRIPTION (Adapted from applicant's abstract): New retinal genes have been
identified and studied in the investigator's laboratory in order to identify
etiologies for hereditary blinding retinal diseases, to study how these genes
cause disease, and to use this information to find the best treatment or cure
for them. To date, it has been demonstrated that: (1) a patient with late-onset
cone-rod dystrophy has a nonsense codon mutation in HRG4, a photoreceptor gene
identified in the investigator's laboratory; (2) a transgenic mouse model
carrying the same mutation as the patient showed an ERG abnormality, consistent
with a problem in neurotransmission at the photoreceptor synapse and late-onset
retinal degeneration; (3) HRG4 is present in the rod and cone photoreceptor
synapses, making it the first synaptic protein implicated in retinal
degeneration; and (4) HRG4 is homologous to UNC119, a mutated protein in C.
elegans with problems of coordination, feeding, and chemosensation. For
continuation of the HRG4 study, 4 aims are proposed. Specific aim 1 will test
the hypothesis that HRG4 plays a significant role in the synaptic vesicle cycle
which forms the basis of synaptic neurotransmission. The status of synaptic
vesicle cycle proteins and their interactions will be compared in the
transgenic model versus normal mice. Aim 2 is to determine the identity of the
partner or target protein with which HRG4 interacts in order to elucidate the
function of HRG4. Direct binding assays, co-immunoprecipitation experiments
using the recombinant HRG4, and the yeast two-hybrid strategy will be used. Aim
3 is to construct an HRG4 gene-targeted (knock-out) mouse model and to study
the effect of null expression of this gene on the phenotype and mechanism of
genesis of the phenotype. The goals of this aim are to (i) investigate the
function and pathogenic mechanism of HRG4 and (ii) to obtain an animal model in
which structure-function studies of HRG4 can be carried out by transgene
expression against a clean background, and which ultimately can be used to
investigate the mechanism and the treatment of retinal degeneration. Aim 4 is
to screen the HRG4 gene for mutations in patients with retinopathies by (a)
searching for patients whose retinopathy has been mapped to 17q11 and screening
them, if found; (b) searching for patients with neurofibromatosis mapping to
17q11.2 and retinopathy and screening them in order to determine the presence
of a contiguous chromosome syndrome and the involvement of HRG4 in the
retinopathy; (c) conducting rapid random mutational screening using denaturing
gradient gel electrophoresis or heteroduplex analysis on unmapped cases of
retinopathy; (d) investigating the possible interaction of mutations in HRG4
and other retinal degeneration genes by screening both; and (e) performing
co-segregation analysis and screening of normal DNA for any mutations found in
order to confirm the pathogenic relationship and establish the significance of
HRG4 for retinal diseases.
Effective start/end date5/1/964/30/05


  • National Eye Institute
  • National Eye Institute: $337,500.00
  • National Eye Institute: $300,000.00
  • National Eye Institute
  • National Eye Institute
  • National Eye Institute
  • National Eye Institute: $300,000.00
  • National Eye Institute: $300,000.00


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