Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families

Sheikh Amer Riazuddin, Fareeha Zulfiqar, Qingjiong Zhang, Yuri V. Sergeev, Zaheeruddin A. Qazi, Tayyab Husnain, Rafael Caruso, Sheikh Riazuddin, Paul A. Sieving, J. Fielding Hejtmancik

Research output: Contribution to journalArticle

Abstract

PURPOSE. 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.

Original languageEnglish (US)
Pages (from-to)2264-2270
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number7
DOIs
StatePublished - 2005
Externally publishedYes

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Retinitis Pigmentosa
Mutation
Inheritance Patterns
Genome
Lod Score
Chromosomes, Human, Pair 8
DNA
Microsatellite Repeats
Signs and Symptoms
Siblings
Exons
Proteins
Parents
Alleles
Genes

ASJC Scopus subject areas

  • Ophthalmology

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Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families. / Riazuddin, Sheikh Amer; Zulfiqar, Fareeha; Zhang, Qingjiong; Sergeev, Yuri V.; Qazi, Zaheeruddin A.; Husnain, Tayyab; Caruso, Rafael; Riazuddin, Sheikh; Sieving, Paul A.; Hejtmancik, J. Fielding.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 7, 2005, p. 2264-2270.

Research output: Contribution to journalArticle

Riazuddin, SA, Zulfiqar, F, Zhang, Q, Sergeev, YV, Qazi, ZA, Husnain, T, Caruso, R, Riazuddin, S, Sieving, PA & Hejtmancik, JF 2005, 'Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families', Investigative Ophthalmology and Visual Science, vol. 46, no. 7, pp. 2264-2270. https://doi.org/10.1167/iovs.04-1280
Riazuddin, Sheikh Amer ; Zulfiqar, Fareeha ; Zhang, Qingjiong ; Sergeev, Yuri V. ; Qazi, Zaheeruddin A. ; Husnain, Tayyab ; Caruso, Rafael ; Riazuddin, Sheikh ; Sieving, Paul A. ; Hejtmancik, J. Fielding. / Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 7. pp. 2264-2270.
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abstract = "PURPOSE. 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.",
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T1 - Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families

AU - Riazuddin, Sheikh Amer

AU - Zulfiqar, Fareeha

AU - Zhang, Qingjiong

AU - Sergeev, Yuri V.

AU - Qazi, Zaheeruddin A.

AU - Husnain, Tayyab

AU - Caruso, Rafael

AU - Riazuddin, Sheikh

AU - Sieving, Paul A.

AU - Hejtmancik, J. Fielding

PY - 2005

Y1 - 2005

N2 - PURPOSE. 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.

AB - PURPOSE. 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.

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