Correlations of Genotype with Phenotype in Indian Patients with Primary Congenital Glaucoma

Panicker, Shirly G.; Mandal, Anil K.; Reddy, Aramati B. M.; Gothwal, Vijaya K.; Hasnain, Seyed E.

doi:10.1167/iovs.03-0404

Cited by 78 publications

(60 citation statements)

References 28 publications

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“…Phenotypic features associated with mutations found among a larger number of both Iranian and Indian patients are presented in Table 3. 35 Only data on homozygous patients are presented so as to eliminate variations attributable to effects of differing second mutations. Data on R390H and R469W are in-cluded because these are common mutations among the Iranian patients.…”

Section: Novel Variationsmentioning

confidence: 99%

CYP1B1 Mutation Profile of Iranian Primary Congenital Glaucoma Patients and Associated Haplotypes

Chitsazian

Tusi

Elahi

et al. 2007

The Journal of Molecular Diagnostics

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The mutation spectrum of CYP1B1 among 104 primary congenital glaucoma patients of the genetically heterogeneous Iranian population was investigated by sequencing. We also determined intragenic single nucleotide polymorphism (SNP) haplotypes associated with the mutations and compared these with haplotypes of other populations. Finally, the frequency distribution of the haplotypes was compared among primary congenital glaucoma patients with and without CYP1B1 mutations and normal controls. Genotype classification of six high-frequency SNPs was performed using the PHASE 2.0 software. CYP1B1 mutations in the Iranian patients were very heterogeneous. Nineteen nonconservative mutations associated with disease, and 10 variations not associated with disease were identified. Ten mutations and three variations not associated with disease were novel. The 13 novel variations make a notable contribution to the ϳ70 known variations in the gene. CYP1B1 mutations were identified in 70% of the patients. The four most common mutations were G61E, R368H, R390H, and R469W, which together constituted 76.2% of the CYP1B1 mutated alleles found. Six unique core SNP haplotypes were identified, four of which were common to the patients with and without CYP1B1 mutations and controls studied.

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Section: Novel Variationsmentioning

confidence: 99%

CYP1B1 Mutation Profile of Iranian Primary Congenital Glaucoma Patients and Associated Haplotypes

Chitsazian

Tusi

Elahi

et al. 2007

The Journal of Molecular Diagnostics

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“…Analysis of compound mutants of Foxc1 and Foxc2, factors with virtually identical DNA-binding domains, demonstrate that in many systems they have redundant function. Interestingly, mutations in FOXC1 were identified in numerous cases as causative for the dominant human disorder Axenfeld-Rieger syndrome (ARS) (7)(8)(9)(10)(11) indicating nonredundant functions for Foxc1 in at least some regions. ARS is characterized by dysgenesis of the anterior segment of the eye and is often associated with craniofacial abnormalities and abnormal dentition.…”

mentioning

confidence: 99%

Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development

Zarbalis

Siegenthaler

Choe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

109

126

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We report the identification of a hypomorphic mouse allele for Foxc1 (Foxc1 hith ) that survives into adulthood revealing previously unknown roles for Foxc1 in development of the skull and cerebral cortex. This line of mice was recovered in a forward genetic screen using ENU mutagenesis to identify mutants with cortical defects. In the hith allele a missense mutation substitutes a Leu for a conserved Phe at amino acid 107, leading to destabilization of the protein without substantially altering transcriptional activity. Embryonic and postnatal histological analyses indicate that diminished Foxc1 protein expression in all three layers of meningeal cells in Foxc1 hith/hith mice contributes to the cortical and skull defects in mutant mice and that the prominent phenotypes appear as the meninges differentiate into pia, arachnoid, and dura. Careful analysis of the cortical phenotypes shows that Foxc1 hith/hith mice display detachment of radial glial endfeet, marginal zone heterotopias, and cortical dyslamination. These abnormalities have some features resembling defects in type 2 (cobblestone) lissencephaly or congenital muscular dystrophies but appear later in corticogenesis because of the delay in breakdown of the basement membrane. Our data reveal that the meninges regulate the development of the skull and cerebral cortex by controlling aspects of the formation of these neighboring structures. Furthermore, we provide evidence that defects in meningeal differentiation can lead to severe cortical dysplasia.genetic screen ͉ meninges ͉ migration

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“…However, the geographical distribution was markedly different, with regional clustering of p.E387K alleles, in contrast to the wide spread of p.R299X (Figure 3). A different history is also suggested by the carrier rates in controls: p.R299X occurs in different Gypsy sub-isolates across Europe at an average rate of B2.4% (Supplementary Table 3), whereas p.E387K has so far not been reported in India, [26][27][28][29] and its carrier rate among Bulgarian Gypsies is only 0.3% with a limited distribution within Bulgaria and apparently also in Europe (Supplementary Table 5 and Figure 3). …”

Section: Population Genetics Of Pcg In Gypsiesmentioning

confidence: 99%

“…42 Such an approach implies continued molecular investigations in cases with only one identified defect. 22,[26][27][28]44 Our current data suggest that the truncating p.R299X mutation in LTBP2 is associated with greater phenotype severity and poorer outcome. Follow-up of this observation should be possible given the increased incidence of PCG in the Gypsies with equal proportions of patients with mutations in the known and yet uncharacterised genes.…”

Section: Population Genetics Of Pcg In Gypsiesmentioning

confidence: 99%

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

et al. 2010

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Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/ Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for B70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations -p.R299X/LTBP2 and p.E387K/CYP1B1.

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Correlations of Genotype with Phenotype in Indian Patients with Primary Congenital Glaucoma

Cited by 78 publications

References 28 publications

CYP1B1 Mutation Profile of Iranian Primary Congenital Glaucoma Patients and Associated Haplotypes

CYP1B1 Mutation Profile of Iranian Primary Congenital Glaucoma Patients and Associated Haplotypes

Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

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