A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa.
X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5' upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in <10% and approximately 20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.
Breuer
Debra K
DK
Department of Human Genetics, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA.
Yashar
Beverly M
BM
Filippova
Elena
E
Hiriyanna
Suja
S
Lyons
Robert H
RH
Mears
Alan J
AJ
Asaye
Bersabell
B
Acar
Ceren
C
Vervoort
Raf
R
Wright
Alan F
AF
Musarella
Maria A
MA
Wheeler
Patricia
P
MacDonald
Ian
I
Iannaccone
Alessandro
A
Birch
David
D
Hoffman
Dennis R
DR
Fishman
Gerald A
GA
Heckenlively
John R
JR
Jacobson
Samuel G
SG
Sieving
Paul A
PA
Swaroop
Anand
A
D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005136:Eye Proteins; D019204:GTP-Binding Proteins; D008040:Genetic Linkage / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D009154:Mutation / Q000235:genetics*; D009656:North America; D016366:Open Reading Frames / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics*
D002352:Carrier Proteins; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; C072178:RP2 protein, human; C099929:RPGR protein, human; D019204:GTP-Binding Proteins