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Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma.

ABSTRACT: PURPOSE: Primary congenital glaucoma (PCG), a severe form of glaucoma that presents early in life, is an autosomal recessive eye disorder that results from defects in anterior eye segment. Null mutations in LTBP2 were reported in patients with PCG in Pakistani and Iranian families. This study was aimed to identify the mutation profile of the LTBP2 gene in north Indian patients with PCG. METHODS: After ethical clearance, 54 unrelated patients with PCG who were either negative or heterozygous for MYOC, CYP1B1, and FOXC1 mutations and 50 ethnically matched non-glaucomatous controls were recruited for the study. PCG diagnosis was established by the presence of buphthalmos in at least one affected eye and associated high intraocular pressure before the age of 3 years. LTBP2 was screened in genomic blood DNA for mutations, with PCR and direct sequencing of PCR amplified fragments. RESULTS: We observed one intronic single nucleotide polymorphism (rs3742793) between exons 6 and 7 in the LTBP2 gene in 18 patients with PCG. This nucleotide change resulted in cytosine (C) being replaced by guanosine (G) at position g.75070493. No pathogenic variants were identified in the LTBP2 gene in our cohort of patients. CONCLUSIONS: LTBP2 gene mutations are not involved in the pathogenesis of primary congenital glaucoma in our patients. Thus, it is important to screen other glaucoma-associated loci and genes for involvement in congenital glaucoma in cases that are either negative or heterozygous for MYOC, CYP1B1, and FOXC1 mutations to have better insight into the disease pathogenesis.

SUBMITTER: Mohanty K

PROVIDER: S-EPMC3559091 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma.

Mohanty Kuldeep K Tanwar Mukesh M Dada Rima R Dada Tanuj T

Molecular vision 20130117

<h4>Purpose</h4>Primary congenital glaucoma (PCG), a severe form of glaucoma that presents early in life, is an autosomal recessive eye disorder that results from defects in anterior eye segment. Null mutations in LTBP2 were reported in patients with PCG in Pakistani and Iranian families. This study was aimed to identify the mutation profile of the LTBP2 gene in north Indian patients with PCG.<h4>Methods</h4>After ethical clearance, 54 unrelated patients with PCG who were either negative or hete ...[more]

PMID: 23378721

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Project description:Primary congenital glaucoma (PCG) is a severe form of glaucoma that presents early in life. PCG is a clinical and genetic entity that is distinct from juvenile forms of glaucoma. Inheritance is usually autosomal recessive and therefore the disease might be more common in societies where consanguinity is high. We studied the prevalence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) and latent-transforming growth factor beta-binding protein 2 (LTBP2) mutations in a group of Saudi PCG patients and attempted to correlate the mutation status with the disease severity.Genomic DNA was collected from 54 unrelated Saudi PCG families (74 patients) who were diagnosed as having PCG by standard ophthalmological examinations and screened for mutations in CYP1B1 and LTBP2 by sequencing. We also examined the effect of mutations on the phenotype of patients with PCG (phenotype-genotype correlation).Mutations in CYP1B1 were identified in 41 (75.9%) of affected patients. No mutation in CYP1B1 was found in 13 (24.1%) affected persons. We detected a total of 13 mutations: 9 missense mutations (G61E, A119S, R390H, P437L, D441G, A443G, G466S, G466D, and R469W), 2 deletions (g.4238_4247del and g.7901_7913del), and 2 nonsense mutations (R355X and R444X). Two mutations, G466S and D441G, were novel. The G61E mutation was by far the most common mutation detected. PCG cases with CYP1B1 mutation(s) presented with a high degree of haze and greater cup/disc ratio than those with no mutation(s). Also, PCG cases with a mutation had higher post operative indices in terms of post operative haze and the need for anti-glaucoma medications. Additionally, the surgical success rate was higher 13/14 (92.9%) among cases without mutation than those with mutation 42/60 (70%). No mutation(s) were found in LTBP2 in any of the tested patients.CYP1B1 mutations are the predominant cause of PCG in the Saudi Arabian population with G61E as the dominant disease-associated allele. PCG cases with a mutation had higher last postoperative visit indices in terms of postoperative haze and the need for anti-glaucoma medications. This will be a valuable parameter in predicting disease severity earlier on and might help in predicting the surgical outcome.

Project description:Primary congenital glaucoma (PСG) is a visual organ pathology that leads to progressive blindness and poor vision in children. Its main cause is an anomaly of the anterior chamber angle. Most cases of PСG are sporadic, but familial cases with an autosomal recessive (predominantly) and autosomal dominant (rare) type of inheritance have been described. Congenital glaucoma is a rare condition (1 case per 10,000-20,000 newborns), but its prevalence is substantially higher (up to 1 case per 250 newborns) in countries where consanguineous marriages are common. Mutations in the CYP1B1 gene, which encodes cytochrome P450 1B1, are the most common cause of autosomal recessive primary congenital glaucoma. This enzyme is known to be involved in retinoic acid metabolism and is necessary for normal eye development. The aim of this work was to assess the polymorphism of the CYP1B1 gene among West Siberian patients with primary congenital glaucoma. Direct automatic Sanger sequencing of exons and adjacent splicing sites of the CYP1B1 gene was carried out in 28 people with the PCG phenotype from a West Siberian region. As a result, in the sample of the white population we examined, pathogenic variants previously described in other ethnic groups were revealed: E387K (rs55989760), R444* (rs377049098), R444Q (rs72549376), and P437L (rs56175199), as well as novel single-nucleotide deletion p.F114Lfs*38 in the CYP1B1 gene. The latter can cause a frame shift, changed amino acid composition, and a formation of truncated in the protein. None of the detected mutations were found in the control sample of ophthalmologically examined individuals without PCG (100 people). Variants R444* (rs377049098) and R444Q (rs72549376) were not found in the general population sample either (576 randomly selected West Siberia residents). All the detected mutations caused the development of the autosomal recessive form of primary congenital glaucoma. The most severe clinical phenotype was observed in carriers of mutations in codon 444 of the gene. Consequently, in children with signs of increased intraocular pressure, molecular genetic analysis of the CYP1B1 gene is advisable for early diagnosis and timely initiation of PCG therapy.

Dataset Information

Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma.

Publications

Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma.

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