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Purpose Peters anomaly (PA) is a heterogeneous developmental disorder characterized by central corneal opacity and iridocorneal or corneolenticular adhesions. Although many causative genes have been identified, most screened patients do not have mutations in the known genes. We aimed to identify the genetic cause of Peters anomaly in a pedigree with three affected individuals. Methods Slit-lamp biomicroscopy and ultrasound biomicroscopy were performed for definitive diagnosis. Exome sequencing was conducted on the DNA of all three patients. After identification of a candidate causative gene, expression of the gene was assessed with real-time PCR in various ocular tissues of three human embryos and three adults. Results The patients were affected with isolated PA. The parents of the patients were related to one another. Inheritance of PA was autosomal recessive. After appropriate filtering of the exome data, a homozygous variation in DOP1B remained as the only candidate genetic cause of PA in the pedigree. The variant segregated with disease status in the pedigree and was absent among 800 control Iranians. The variant has been reported in various databases at frequencies of 0.006 or less only in the heterozygous state in some cohorts of African origin. The p.Val1660 amino acid affected by the mutation is completely conserved in mammals and birds during evolution. Expression of DOP1B was shown in all adult and embryonic lens, iris, cornea, sclera, and retina tissues that were tested. Conclusions DOP1B that encodes DOP1 leucine zipper like protein B was identified as the putative PA-causing gene in pedigree PA-101. As DOP1B is positioned within the Down syndrome chromosomal region on chromosome 21, until now this gene has mostly been studied with respect to brain functions. However, members of the Dopey gene family have been shown to have roles in development in other organisms. Evidence of the expression of DOP1B in various PA-relevant eye tissues, which, to the best of our knowledge, is shown here for the first time, is to be noted. However, this finding does not necessarily implicate a specific role for DOP1B in eye development as the gene is expressed in many tissues. Ultimately, definitive assessment of the contribution of DOP1B to PA pathology awaits identification of mutations in the gene in unrelated patients with PA and functional studies.

Purpose To assess whether loci other than GLC3A, GLC3B, and GLC3C are linked to primary congenital glaucoma (PCG). Methods The gene CYP1B1 at GLC3A was screened in 19 Iranian PCG probands who had been recruited mostly from among individuals of Turkish ethnicity and individuals from central and eastern Iran. The gene MYOC was screened in patients from this cohort who lacked CYP1B1 mutations and in ten patients previously shown not to carry CYP1B1 mutations. Family members of 19 probands without mutations in either of these genes were recruited for assessment of linkage to GLC3B and GLC3C by genotyping microsatellite markers. In total, 127 individuals, including 35 affected with PCG, were genotyped. Results Eleven (57.9%) of the newly recruited PCG patients did not carry disease-associated mutations in CYP1B1. Disease-associated MYOC mutations were not observed in any of the patients screened. Inheritance of PCG in all the families was consistent with an autosomal recessive pattern. Linkage to GLC3B and GLC3C was ruled out in nine of the families on the basis of autozygosity mapping and haplotype analysis. Conclusions Observation of the absence of linkage to GLC3B and GLC3C in at least nine families without CYP1B1 mutations suggests that at least one PCG-causing locus other than GLC3A, GLC3B, and GLC3C may exist. The disease-causing gene or genes in the novel locus or loci may account for PCG in a notable fraction of Iranian patients.

Purpose The gene coding cytochrome P4501B1 (CYP1B1) has been shown to be a major cause of primary congenital glaucoma in the Iranian population. More recently it was shown to also be important in juvenile-onset open angle glaucoma (JOAG). We aimed to further investigate the role of CYP1B1 in a larger cohort of primary open angle glaucoma (POAG) patients which included late-onset patients. We also aimed to set up a microarray based protocol for mutation screening with an intent of using the protocol in a future population level screening program. Methods Sixty three POAG patients, nine affected family members, and thirty three previously genotyped primary congenital glaucoma (PCG) patients were included in the study. Clinical examination included slit lamp biomicroscopy, IOP measurement, gonioscopic evaluation, fundus examination, and measurement of perimetry. G61E, R368H, R390H, and R469W were screened by a protocol that included multiplexed allele specific amplification in the presence of a protease (PrASE), use of sequence tagged primers, and hybridization to generic arrays on microarray slides. The entire coding sequences of CYP1B1 and myocilin (MYOC) genes were sequenced in all individuals assessed by the microarray assay to carry a mutation. Intragenic single nucleotide polymorphism (SNP) haplotpes were determined for mutated alleles. Results Genotypes assessed by the array-based PrASE methodology were in 100% concordance with sequencing results. Seven mutation carrying POAG patients (11.1%) were identified, and their distribution was quite skewed between the juvenile-onset individuals (5/21) as compared to late-onset cases (2/42). Four of the seven mutation carrying Iranian patients harbored two mutated alleles. CYP1B1 mutated alleles in Iranian PCG and POAG patients shared common haplotypes. MYOC mutations were not observed in any of the patients. Conclusions The PrASE approach allowed reliable simultaneous genotyping of many individuals. It can be an appropriate tool for screening common mutations in large sample sizes. The results suggest that CYP1B1 is implicated in POAG among Iranians, notably in the juvenile-onset form. Contrary to POAG patients studied in other populations, many mutation harboring Iranian patients carry two mutated alleles. We propose an explanation for this observation.

Purpose: To assess the frequency of mutations in the Myocilin (MYOC) gene in Iranian patients affected with primary congenital glaucoma (PCG). Methods: The individuals evaluated herein are among a larger cohort of 100 patients who had previously been screened for CYP1B1 mutations. Eighty subjects carried mutations in CYP1B1, but the remaining 20 patients who did not, underwent screening for MYOC mutations for the purpose of the study. MYOC exons in the DNA were polymerase chain reaction (PCR) amplified and sequenced. Sequencing was performed using PCR primers, the ABI big dye chemistry and an ABI3730XL instrument. Sequences were analyzed by comparing them to reference MYOC sequences using the Sequencher software. Results: Four MYOC sequence variations were observed among the patients, but none of them were considered to be associated with disease status. Three of these variations were single nucleotide polymorphisms already reported not to be disease causing, the fourth variation created a synonymous codon and did not affect any amino acid change. Conclusion: In this cohort, MYOC mutations were not observed in any Iranian subject with PCG. It is possible that in a larger sample, a few subjects carrying disease causing MYOC mutations could have been observed. But our results show that the contribution of MYOC to PCG status in Iran is small if any.

Previous work has indicated that radiation doses from deposition on human skin, hair and clothing may contribute significantly to the dose received after a major nuclear accident, such as that, which happened at Chernobyl in 1986. The available data was,however, sparse and associated with considerable variation, clearly showing a need for further investigations to verify preliminary conclusions, examine processes in greater detail and identify important factors causing the observed parameter variation.For instance, the impacts of thermophoresis, electrophoresis, skin moisture and wind speed on the deposition of contaminant aerosol were examined, and since the previous measurements had indicated that elemental iodine could be a particularly problematiccontaminant, experimental work was additionally undertaken to examine the process of deposition of this species to skin. Since both clearance and percutaneous penetration of deposited contaminants could play important roles in determining doses,experimental programmes were dedicated to the identification of parameters of interest in these contexts. Also doses from contamination on different surfaces in the indoor environment have in the past traditionally been neglected, and a theoreticalapproach, based on measurements, was developed for accurate prediction of these doses under different conditions. Also resuspension of deposited matter and its role in dose formation, by subsequent deposition or inhalation, was investigated throughexperiments. Contact transfer of contaminants from an indoor surface to human skin may give yet another contribution to dose and also the relevant parameters in this direction were examined experimentally. The ultimate goal of the investigations was toenable the determination of the various contributions to dose in a contaminated indoor environment. A model methodology was developed and an example of its use was given. It was found that after a major nuclear accident, doses from indoor deposition tohumans, deposition on indoor surfaces and inhalation in the indoor environment would all be important to consider. Previous work has indicated that radiation doses from deposition on human skin, hair and clothing may contribute significantly to the dose received after a major nuclear accident, such as that, which happened at Chernobyl in 1986. The available data was, however, sparse and associated with considerable variation, clearly showing a need for further investigations to verify preliminary conclusions, examine processes in greater detail and identify important factors causing the observed parameter variation. For instance, the impacts of thermophoresis, electrophoresis, skin moisture and wind speed on the deposition of contaminant aerosol were examined, and since the previous measurements had indicated that elemental iodine could be a particularly problematic contaminant, experimental work was additionally undertaken to examine the process of deposition of this species to skin. Since both clearance and percutaneous penetration of deposited contaminants could play important roles in determining doses, experimental programmes were dedicated to the identification of parameters of interest in these contexts. Also doses from contamination on different surfaces in the indoor environment have in the past traditionally been neglected, and a theoretical approach, based on measurements, was developed for accurate prediction of these doses under different conditions. Also resuspension of deposited matter and its role in dose formation, by subsequent deposition or inhalation, was investigated through experiments. Contact transfer of contaminants from an indoor surface to human skin may give yet another contribution to dose and also the relevant parameters in this direction were examined experimentally. The ultimate goal of the investigations was to enable the determination of the various contributions to dose in a contaminated indoor environment. A model methodology was developed and an example of its use was given. It was found that after a major nuclear accident, doses from indoor deposition to humans, deposition on indoor surfaces and inhalation in the indoor environment would all be important to consider.