Diagnosis of autosomal dominant retinitis pigmentosa by linkage-based exclusion screening with multiple locus-specific microsatellite markers.
OBJECTIVE
To describe a hierarchical approach for efficient genetic diagnosis of autosomal dominant retinitis pigmentosa (adRP).


METHODS
Forty di-, tri-, or tetra-nucleotide repeats tightly linked to 10 genes known to be responsible for adRP were identified from the human genome sequence and used as markers in multiplex amplification and genotyping, followed by linkage analysis. Discordance of cosegregation of markers and the disease excluded the majority of the examined genes as candidates, and mutation screening for the remaining genes was performed.


RESULTS
With this strategy, examination of an adRP-affected family indicated that 3 of 10 candidate genes segregated concordantly with the disease. Further searches for mutations revealed a novel insertion and deletion in the last exon of a splicing factor gene, PRPF8.


CONCLUSIONS
This systematic approach facilitates the molecular diagnosis of adRP, which is known to have a highly heterogeneous genetic background.
Kondo
Hiroyuki
H
Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, Japan. hkondo@fukuoka-u.ac.jp
Tahira
Tomoko
T
Mizota
Atsushi
A
Adachi-Usami
Emiko
E
Oshima
Kenji
K
Hayashi
Kenshi
K
D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005799:Genes, Dominant; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D016601:RNA-Binding Proteins; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D020080:Tandem Repeat Sequences
D002352:Carrier Proteins; C115374:PRPF8 protein, human; D016601:RNA-Binding Proteins; D004247:DNA