Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families.
OBJECTIVE
To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families.


METHODS
Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated.


RESULTS
A genome-wide scan of 25 families gave an hlod = 4.53 with D8S260. Retinitis pigmentosa in all three families mapped to a 14.21-cM (21.19-Mb) region on chromosome 8 at q11, flanked by D8S532 and D8S260. This region harbors RP1, which is known to cause autosomal dominant retinitis pigmentosa. Sequencing of the coding exons of RP1 showed mutations in all three families: two single-base deletions, c.4703delA and c.5400delA, resulting in a frame shift, and a 4-bp insertion, c.1606insTGAA, all causing premature termination of the protein. All affected individuals in these families are homozygous for the mutations. Parents and siblings heterozygous for the mutant allele did not show any signs or symptoms of RP.


CONCLUSIONS
These results provide strong evidence that mutations in RP1 can result in recessive as well as dominant retinitis pigmentosa. The findings suggest that truncation of RP1 before the BIF motif or within the terminal portion results in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or immediately after the BIF domain may result in a protein with a deleterious effect and hence a dominant inheritance pattern.
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
S Amer
SA
Riazuddin
Fareeha
F
Zulfiqar
Qingjiong
Q
Zhang
Yuri V
YV
Sergeev
Zaheeruddin A
ZA
Qazi
Tayyab
T
Husnain
Rafael
R
Caruso
Sheikh
S
Riazuddin
Paul A
PA
Sieving
J Fielding
JF
Hejtmancik
D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D008040:Genetic Linkage; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008869:Microtubule-Associated Proteins; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012174:Retinitis Pigmentosa / Q000208:ethnology / Q000235:genetics* / Q000473:pathology
D018389:Codon, Nonsense; D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; C120042:RP1 protein, human