Evaluation of the G protein coupled receptor-75 (GPR75) in age related macular degeneration
Christian G Sauera, Karen Whitea, Heidi Stöhra, Tiemo Grimma, Amy Hutchinsonb, Paul S Bernsteinc, Richard Allan Lewisd, Francesca Simonellie, Daniel Pauleikhofff, Rando Allikmetsb, Bernhard H F Webera
a Institute of Human
Genetics, University of Würzburg, Germany, b Departments of Ophthalmology and Pathology,
Columbia University, New York, NY, USA, c Moran Eye Center, University of Utah,
Salt Lake City, UT, USA, d Departments
of Ophthalmology and of Molecular and Human Genetics, Baylor College of
Medicine, Houston, TX, USA, e Eye
Clinic, Second University of Naples, Italy, f Augenabteilung, St Franziskus-Hospital,
Münster, Germany
Correspondence to: Bernhard H F Weber, Institute of Human Genetics, Biocenter, Am Hubland, D-97074 Würzburg, Germany bweb{at}biozentrum.uni-wuerzburg.de
Accepted for publication 8 March 2001
BACKGROUND
A long term
project was initiated to identify and to characterise genes that are
expressed exclusively or preferentially in the retina as candidates for
a genetic susceptibility to age related macular degeneration (AMD). A
transcript represented by a cluster of five human expressed sequence
tags (ESTs) derived exclusively from retinal cDNA libraries was identified.
METHODSNorthern blot
and RT-PCR analyses confirmed preferential retinal expression of the
gene, which encodes a G protein coupled receptor, GPR75. Following
isolation of the full length cDNA and determination of the genomic
organisation, the coding sequence of GPR75
was screened for mutations in 535 AMD patients and 252 controls
from Germany, the United States, and Italy. Employed methods included
single stranded conformational polymorphism (SSCP) analysis, denaturing
high performance liquid chromatography (DHPLC), and direct sequencing.
RESULTSNine different
sequence variations were identified in patients and control
individuals. Three of these (-30A>C, 150G>A, and 346G>A) likely
represent polymorphic variants. Each of six alterations (-4G>A, N78K,
P99L, S108T, T135P, and Q234X) were found once in single AMD patients
and were considered variants that could affect the protein function and
potentially cause retinal pathology.
CONCLUSIONThe
presence of six potential pathogenic variants in a cohort of 535 AMD
patients alone does not provide statistically significant evidence for
the association of sequence variation in GPR75
with genetic predisposition to AMD. However, a possible
connection between the variants and age related retinal pathology
cannot be discarded. Functional studies are needed to clarify the role of GPR75 in retinal physiology.
© 2001 by British Journal of Ophthalmology
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