TY - JOUR
T1 - Mutations in βB3-crystallin associated with autosomal recessive cataract in two Pakistani families
AU - Riazuddin, S. 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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U2 - 10.1167/iovs.04-1481
DO - 10.1167/iovs.04-1481
M3 - Article
C2 - 15914629
AN - SCOPUS:22144453269
SN - 0146-0404
VL - 46
SP - 2100
EP - 2106
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 6
ER -