《Table 3 CYP1B1 mutations found in PCG patients of Pakistani origin》

《Table 3 CYP1B1 mutations found in PCG patients of Pakistani origin》   提示:宽带有限、当前游客访问压缩模式
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《Two novel variants in CYP1B1 gene: a major contributor of autosomal recessive primary congenital glaucoma with allelic heterogeneity in Pakistani patients》


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NA:Not available.aReported first in Pakistani PCG patients.

Five pathogenic CYP1B1 variants were segregating with PCG in 7 families(7/11),including two novel mutations.p.R390H was found in four families(4/7;57%),thus remained the most common variant.It supported the previous finding of p.R390H(50%)in the cohort of 20 PCG affected families[11].p.R390H has remained the frequent CYP1B1 variant causing PCG among patients of different ethnic backgrounds of Pakistan.All our patients carrying p.R390H belonged to Sindhi Ethnic group,whereas a recent study based on PCG patients of Punjabi ethnicity also reported the highest frequency of p.R390H(13/23;57%)[17].The overall frequency of p.R390H is 46%(45/102)when combined all the Pakistani patients having CYP1B1 associated PCG(Table 3)and is higher than neighboring world populations[18-20].p.R390H also show phenotypic variability among Pakistani patients;It has been associated with Juvenile-onset open angle glaucoma and with primary open angle glaucoma in a single Pakistani family[21-22].In this study,27 affected individuals from four p.R390H mutated consanguineous families have age ranging from 2.5y to 42y.All the patient had onset of bilateral glaucoma in first three years of life.The patients without any surgical intervention had vision loss along with corneal opacities,elevated IOP and increased CDR thus indicating the importance of timely surgical intervention for prevention of glaucoma symptoms and restoration of vision.Furthermore,all the individuals carrying single allele of p.R390H were phenotypically normal.p.P437L is the second known mutation found in two affected members of the family PCG24(Figure 1).This CYP1B1variant was first reported in the homozygous state in a Turkish PCG affected family[23],and as compound heterozygous in Brazilian patients[24].p.P437L has been first time reported in PCG patients with Pakistani origin.The different clinical presentation was observed in both affected:the patient IV:1had bilateral corneal opacity,whereas patient IV:2 had clear cornea in both eyes(Table 2).Although trabeculectomy was done in both affected but the patient IV:1 had elevated IOP.This is contrary to the patients homozygous for p.R390H,where the IOP was controllable after trabeculectomy(Table 1).This indicates that there may be other factors,responsible for clinical variations in the PCG patients.Moreover,functional characterization of p.P437L shows that it affects only the enzyme activity and there is no impact on intracellular localization and folding of the protein[23,25].Whereas,p.R390H,substitution may lead to in disruption of salt bridge formation and normal functioning of the CYP1B1 protein[26].This difference in position of both residues may also be responsible for variable clinical presentation.