Mutations in βB3-crystallin associated with autosomal recessive cataract in two Pakistani families

Sheikh Amer Riazuddin, Afshan Yasmeen, Wenliang Yao, Yuri V. Sergeev, Qingjiong Zhang, Fareeha Zulfiqar, Assad Riaz, Sheikh Riazuddin, J. Fielding Hejtmancik

Research output: Contribution to journalArticle

Abstract

PURPOSE. To identify the disease locus for autosomal recessive congenital cataracts in consanguineous Pakistani families. METHODS. Two Pakistani families were ascertained, patients were examined, blood samples were collected, and DNA was isolated. A genome-wide scan was performed using >382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. Two-point lod scores were calculated, haplotypes were formed by inspection, and candidate genes were sequenced. Real-time quantitative PCR techniques were used to determine the mRNA levels, and molecular modeling was performed to gain a better understanding of the significance of the disease-causing mutation. RESULTS. In the genome-wide scan, maximum lod scores of 2.67 and 2.77 for family 60004 and 2.02 and 2.04 for family 60006 were obtained for markers D22S539 and D22S315, respectively. The linked region, 22.7 cM (10 Mb) flanked by markers D22S420 and D22S1163, contains the β-crystallin gene cluster including the genes CRYBA4, CRYBB1, CRYBB2, and CRYBB3. Sequencing of these genes showed a G→C transition in exon 6 of CRYBB3 resulting in a p.G165R change in the βB3-crystallin protein that cosegregates with the disease in both families. Real-time PCR analysis suggested that βB3-crystallin mRNA levels approximate those of other βγ-crystallins. Molecular modeling predicted changes in electrostatic potential that would be expected to reduce the stability of the fourth Greek-key motif, and hence the entire protein, dramatically. CONCLUSIONS. For the first time, a mutation in CRYBB3 is reported in two consanguineous Pakistani families with autosomal recessive congenital cataracts.

Original languageEnglish (US)
Pages (from-to)2100-2106
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number6
DOIs
StatePublished - Jun 2005
Externally publishedYes

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Crystallins
Cataract
Mutation
Lod Score
Real-Time Polymerase Chain Reaction
Genome
Genes
Messenger RNA
DNA
Multigene Family
Static Electricity
Microsatellite Repeats
Haplotypes
Exons
Proteins

ASJC Scopus subject areas

  • Ophthalmology

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Mutations in βB3-crystallin associated with autosomal recessive cataract in two Pakistani families. / Riazuddin, Sheikh Amer; Yasmeen, Afshan; Yao, Wenliang; Sergeev, Yuri V.; Zhang, Qingjiong; Zulfiqar, Fareeha; Riaz, Assad; Riazuddin, Sheikh; Hejtmancik, J. Fielding.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 6, 06.2005, p. 2100-2106.

Research output: Contribution to journalArticle

Riazuddin, SA, Yasmeen, A, Yao, W, Sergeev, YV, Zhang, Q, Zulfiqar, F, Riaz, A, Riazuddin, S & Hejtmancik, JF 2005, 'Mutations in βB3-crystallin associated with autosomal recessive cataract in two Pakistani families', Investigative Ophthalmology and Visual Science, vol. 46, no. 6, pp. 2100-2106. https://doi.org/10.1167/iovs.04-1481
Riazuddin, Sheikh Amer ; Yasmeen, Afshan ; Yao, Wenliang ; Sergeev, Yuri V. ; Zhang, Qingjiong ; Zulfiqar, Fareeha ; Riaz, Assad ; Riazuddin, Sheikh ; Hejtmancik, J. Fielding. / Mutations in βB3-crystallin associated with autosomal recessive cataract in two Pakistani families. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 6. pp. 2100-2106.
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T1 - Mutations in βB3-crystallin associated with autosomal recessive cataract in two Pakistani families

AU - Riazuddin, Sheikh Amer

AU - Yasmeen, Afshan

AU - Yao, Wenliang

AU - Sergeev, Yuri V.

AU - Zhang, Qingjiong

AU - Zulfiqar, Fareeha

AU - Riaz, Assad

AU - Riazuddin, Sheikh

AU - Hejtmancik, J. Fielding

PY - 2005/6

Y1 - 2005/6

N2 - PURPOSE. To identify the disease locus for autosomal recessive congenital cataracts in consanguineous Pakistani families. METHODS. Two Pakistani families were ascertained, patients were examined, blood samples were collected, and DNA was isolated. A genome-wide scan was performed using >382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. Two-point lod scores were calculated, haplotypes were formed by inspection, and candidate genes were sequenced. Real-time quantitative PCR techniques were used to determine the mRNA levels, and molecular modeling was performed to gain a better understanding of the significance of the disease-causing mutation. RESULTS. In the genome-wide scan, maximum lod scores of 2.67 and 2.77 for family 60004 and 2.02 and 2.04 for family 60006 were obtained for markers D22S539 and D22S315, respectively. The linked region, 22.7 cM (10 Mb) flanked by markers D22S420 and D22S1163, contains the β-crystallin gene cluster including the genes CRYBA4, CRYBB1, CRYBB2, and CRYBB3. Sequencing of these genes showed a G→C transition in exon 6 of CRYBB3 resulting in a p.G165R change in the βB3-crystallin protein that cosegregates with the disease in both families. Real-time PCR analysis suggested that βB3-crystallin mRNA levels approximate those of other βγ-crystallins. Molecular modeling predicted changes in electrostatic potential that would be expected to reduce the stability of the fourth Greek-key motif, and hence the entire protein, dramatically. CONCLUSIONS. For the first time, a mutation in CRYBB3 is reported in two consanguineous Pakistani families with autosomal recessive congenital cataracts.

AB - PURPOSE. To identify the disease locus for autosomal recessive congenital cataracts in consanguineous Pakistani families. METHODS. Two Pakistani families were ascertained, patients were examined, blood samples were collected, and DNA was isolated. A genome-wide scan was performed using >382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. Two-point lod scores were calculated, haplotypes were formed by inspection, and candidate genes were sequenced. Real-time quantitative PCR techniques were used to determine the mRNA levels, and molecular modeling was performed to gain a better understanding of the significance of the disease-causing mutation. RESULTS. In the genome-wide scan, maximum lod scores of 2.67 and 2.77 for family 60004 and 2.02 and 2.04 for family 60006 were obtained for markers D22S539 and D22S315, respectively. The linked region, 22.7 cM (10 Mb) flanked by markers D22S420 and D22S1163, contains the β-crystallin gene cluster including the genes CRYBA4, CRYBB1, CRYBB2, and CRYBB3. Sequencing of these genes showed a G→C transition in exon 6 of CRYBB3 resulting in a p.G165R change in the βB3-crystallin protein that cosegregates with the disease in both families. Real-time PCR analysis suggested that βB3-crystallin mRNA levels approximate those of other βγ-crystallins. Molecular modeling predicted changes in electrostatic potential that would be expected to reduce the stability of the fourth Greek-key motif, and hence the entire protein, dramatically. CONCLUSIONS. For the first time, a mutation in CRYBB3 is reported in two consanguineous Pakistani families with autosomal recessive congenital cataracts.

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