Loss of Motor Protein MYO1C Causes Rhodopsin Mislocalization and Results in Impaired Visual Function.

Unconventional myosins, linked to deafness, are also proposed to play a role in retinal cell physiology. However, their direct role in photoreceptor function remains unclear. We demonstrate that systemic loss of the unconventional myosin MYO1C in mice, specifically causes rhodopsin mislocalization, leading to impaired visual function. Electroretinogram analysis of Myo1c knockout (Myo1c-KO) mice showed a progressive loss of photoreceptor function. Immunohistochemistry and binding assays demonstrated MYO1C localization to photoreceptor inner and outer segments (OS) and identified a direct interaction of rhodopsin with MYO1C. In Myo1c-KO retinas, rhodopsin mislocalized to rod inner segments (IS) and cell bodies, while cone opsins in OS showed punctate staining. In aged mice, the histological and ultrastructural examination of the phenotype of Myo1c-KO retinas showed progressively shorter photoreceptor OS. These results demonstrate that MYO1C is important for rhodopsin localization to the photoreceptor OS, and for normal visual function.

Elevated Plasma Level of 8-Hydroxy-2'-deoxyguanosine Is Associated with Primary Open-Angle Glaucoma.

PURPOSE: To determine the association between plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, a marker for oxidative DNA damage, and patients with primary open-angle glaucoma (POAG) or its clinical phenotypes. Furthermore, we also examined the utility of plasma 8-OHdG as a potential biomarker in POAG. MATERIALS AND METHODS: In a retrospective case-control study, plasma samples were obtained from 50 POAG cases and 45 glaucoma-free controls matched for age, sex, and ethnicity. 8-OHdG levels were measured in duplicate using an enzyme-linked immunosorbent assay (ELISA) on an automated ELISA analyzer. RESULTS: There was no significant difference in age, sex, and systemic disease distribution between POAG cases and controls. Both mean and median 8-OHdG levels were significantly elevated in POAG cases and male subjects. The area under the receiver operating characteristic (ROC) curve value for plasma 8-OHdG was 0.653 (95% confidence interval = 0.54-0.76, p = 0.010). The cutoff values based on quartile distribution and ROC curve analysis showed that elevated plasma 8-OHdG significantly increased the risk of POAG by more than 4-folds. Plasma 8-OHdG had a sensitivity of 78% and specificity of 53%. In logistic regression analysis, 8-OHdG showed a significant effect on POAG outcome (p = 0.016) independent of age, sex, smoking, and systemic diseases. However, no significant correlation was observed between 8-OHdG and specific clinical markers of glaucoma such as intraocular pressure (p = 0.699), cup/disc ratio (p = 0.213), and the number of antiglaucoma medications (p = 0.603). CONCLUSION: The study shows that there is a significant association between elevated plasma 8-OHdG and POAG, supporting the role of systemic oxidative stress-induced DNA damage in POAG pathogenesis. However, with a high rate of false-positivity, plasma 8-OHdG may lack the ability to serve as a potential biomarker in POAG. Further studies in a much larger cohort are needed to confirm these findings.

Association of endothelial nitric oxide synthase (NOS3) gene polymorphisms with primary open-angle glaucoma in a Saudi cohort.

AIM: To investigate the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms in patients with primary open-angle glaucoma (POAG) of Saudi origin. METHODS: This case-control study included 173 patients with POAG (94 men and 79 women) and 171 controls (98 men and 73 women). Genotyping of rs2070744 (T-786C) and rs1799983 (G894T) variants of the NOS3 gene was performed using TaqMan® assay. RESULTS: Rs1799983 genotypes showed a significant association with POAG but did not survive Bonferroni correction (pcorrection = 0.01). The minor 'T' allele was significantly associated with the risk of POAG among men (p = 0.025, odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.07-2.94). Likewise, the genotypes were significantly associated with POAG among men in dominant (p = 0.030, OR = 1.92, 95% CI = 1.06-3.48) and log-additive models (p = 0.022, OR = 1.82, 95% CI = 1.08-3.07), and after adjustment for age and smoking. Genotype and allele frequencies of rs2070744 were not significantly different between POAG cases and controls, and after sex stratification. CG haplotype was significantly protective (p = 0.011, OR = 0.52, 95% CI = 0.32-0.87) and CT haplotype conferred significantly increased risk of POAG (p = 0.016, OR = 2.60, 95% CI = 1.16-5.82) among men. Rs1799983 showed trend (p = 0.054) towards risk of POAG independent of age, gender, smoking, and rs2070744 polymorphism in logistic regression analysis. Both the polymorphisms showed no association with POAG phenotypes such as intraocular pressure and cup/disc ratio. CONCLUSION: Our results suggest that the polymorphism rs1799983 and the haplotypes of rs20707440 and rs1799983 in the NOS3 gene may significantly modulate the risk of POAG in Saudi's, particularly among men. Further larger studies are needed to confirm these findings.

Leber congenital amaurosis: Current genetic basis, scope for genetic testing and personalized medicine.

Retinal dystrophies are one of the leading causes of pediatric congenital blindness. Leber's congenital amaurosis (LCA) encompasses one of the most severe forms of inherited retinal dystrophy responsible for early-onset childhood blindness in infancy. These are clinically characterized by nystagmus, amaurotic pupil response and markedly reduced or in most instances completely absent full-field electroretinogram. LCA exhibits immense genetic heterogeneity. With advances in next-generation genetic technologies, tremendous progress has been achieved over the last two decades in discovering genes and genetic defects leading to retinal dystrophies. Currently, 28 genes have been implicated in the pathogenesis of LCA and with initial reports of success in management with targeted gene therapy the disease has attracted a lot of research attention in the recent time. The review provides an update on genetic basis of LCA, scope for genetic testing and pharmacogenetic medicine in diagnosis and treatment of these diseases.

Association of increased levels of plasma tumor necrosis factor alpha with primary open-angle glaucoma.

PURPOSE: Retinal ganglion cell (RGC) death is a key feature of glaucoma. Elevated levels of tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, can induce RGC apoptosis and play a critical role in glaucomatous neurodegeneration. Based on the possible role of inflammation and oxidative stress in the pathogenesis of primary open-angle glaucoma (POAG), we investigated the association between plasma levels of TNF-α and POAG or its clinical indices in comparison to non-glaucomatous controls. PATIENTS AND METHODS: In a case-control retrospective cohort of 51 POAG cases and 88 controls, plasma TNF-α levels were measured using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on an automated ELISA analyzer. RESULTS: Mean TNF-α level was significantly elevated in POAG cases (1.88 ± 2.17 pg/mL) than the controls (0.93 ± 1.49 pg/mL; p = 0.003). The overall dose-response trend was significant (χ2 = 6.12, df = 2; p = 0.047). No statistical difference was seen in age, gender and systemic disease distribution. A modest negative and significant correlation was seen between TNF-α level and number of antiglaucoma medications, an important clinical index of POAG severity. Moreover, logistic regression analysis showed that the risk of POAG was most significantly affected by TNF-α level and not by age and sex. CONCLUSION: High systemic level of an inflammatory cytokine, TNF-α, is associated with POAG; however, its possible use as a biomarker for early glaucoma diagnosis and/or disease severity needs further investigation.

Elevated levels of plasma tumor necrosis factor alpha in patients with pseudoexfoliation glaucoma.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine, which plays a role in glaucomatous neurodegeneration. Based on the plausible role of inflammation in the pathogenesis of pseudoexfoliation glaucoma (PEG), we investigated whether there is any relationship between the levels of plasma TNF-α and PEG or any of its clinical indices in comparison to normal controls. METHODS: The study was designed as a retrospective analysis. Plasma samples from 49 PEG patients and 88 non-glaucomatous controls were evaluated for TNF-α levels using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on a biochemical/ELISA analyzer. RESULTS: The two study groups were similar in age, sex and systemic disease distribution. The mean TNF-α concentration was significantly higher in the PEG patients (5.54±4.58 pg/mL) than in the control subjects (0.93±1.49 pg/mL; 95% confidence interval [CI] =3.50-5.72; p=0.000). The overall dose-response trend was significant (χ2=57.07, df=2; p=0.000). A moderate positive and significant correlation was seen between TNF-α level and cup/disc ratio, an important clinical index for PEG. Besides, binary logistic regression analysis showed that the risk of PEG was most significantly affected by TNF-α level as compared to no association with age and sex. In receiver operating characteristic analysis, the area under the curve was 0.777 (95% CI =0.682-0.872) and statistically significant (p=0.000). CONCLUSION: Elevated systemic levels of inflammatory marker, TNF-α, are associated with PEG and may possibly serve as a biomarker for undiagnosed early glaucoma and/or as a marker for disease progression.

Polymorphism rs11656696 in GAS7 Is Not Associated with Primary Open Angle Glaucoma in a Saudi Cohort.

AIMS: To conduct a case-control study to investigate the association between the polymorphism rs11656696 located in the growth arrest-specific 7 gene (GAS7)on human chromosome 17p13.1 and primary open angle glaucoma (POAG). METHODS: The polymorphism rs11656696 was genotyped using the TaqMan® assay in 187 subjects comprising 92 unrelated POAG cases and 95 controls of Saudi Arabian origin. RESULTS: Association analysis between cases and controls revealed no significant genotype distribution under additive (p = 0.225), dominant (p = 0.635), or recessive (p = 0.085) models. Moreover, the allele frequency distribution was also nonsignificant (p = 0.70). The minor "A" allele frequency was 0.35 and 0.41 among POAG cases and controls, respectively. In addition, specific clinical indices used to assess severity of glaucoma such as intraocular pressure (IOP), cup/disk ratio, and number of antiglaucoma medications also did not show any significant genotype distribution in POAG cases. Moreover, a binary logistic regression analysis did not show any significant effect of age, sex, or genotype on disease outcome. CONCLUSION: Polymorphism rs11656696 is not associated with POAG nor any of its endophenotypic traits such as IOP and cup/disk ratio and is thus not a risk factor for POAG in this Saudi cohort.

Resveratrol and Ophthalmic Diseases.

Resveratrol, a naturally occurring plant polyphenol found in grapes, is the principal biologically active component in red wine. Clinical studies have shown that resveratrol due to its potent anti-oxidant and anti-inflammatory properties are cardio-protective, chemotherapeutic, neuroprotective, and display anti-aging effects. Oxidative stress and inflammation play a critical role in the initiation and progression of age-related ocular diseases (glaucoma, cataract, diabetic retinopathy and macular degeneration) that lead to progressive loss of vision and blindness. In vitro and in vivo (animal model) experimental studies performed so far have provided evidence for the biological effects of resveratrol on numerous pathways including oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, pro-survival or angiogenesis that are implicated in the pathogenesis of these age-related ocular disorders. In this review, we provide a brief overview of current scientific literature on resveratrol, its plausible mechanism(s) of action, its potential use and current limitations as a nutritional therapeutic intervention in the eye and its related disorders.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

PURPOSE: We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems. METHODS: The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene. RESULTS: The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene. CONCLUSIONS: This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.

Molecular Karyotyping of a Dysmorphic Girl from Saudi Arabia with CYP1B1-negative Primary Congenital Glaucoma.

PURPOSE: To report the results of molecular karyotyping for a dysmorphic girl with CYP1B1-negative primary congenital glaucoma from Saudi Arabia, where CYPB1 mutations account for over 90% of cases of primary congenital glaucoma and the remaining cases are idiopathic. METHODS: CYP1B1 sequencing in the affected child; high-resolution array comparative genomic hybridization (array CGH) of the affected child and both unaffected parents (Affymetrix Cytogenetics Whole-Genome 2.7M array; Affymetrix Inc., Santa Clara, CA, USA). RESULTS: The girl did not harbor CYP1B1 mutation by Sanger sequencing. Array CGH revealed 2 de novo 7p heterozygous duplications (7p21 - 7p14, encompassing 223 genes, and 7p14-7p11.2, encompassing 225 genes) and a 4p homozygous microdeletion (4p14) encompassing one gene only, DTHD1. CONCLUSIONS: The fact that this dysmorphic girl is Saudi Arabian and has CYP1B1-negative primary congenital glaucoma suggests that her glaucoma phenotype is related to her de novo copy number variation. Loss or gain of one or more of the genes encompassed in the identified chromosomal areas may be associated with primary congenital glaucoma and/or other observed phenotypic features.

MicroRNA profiling in intraocular medulloepitheliomas.

PURPOSE: To study the differential expression of microRNA (miRNA) profiles between intraocular medulloepithelioma (ME) and normal control tissue (CT). MATERIAL AND METHODS: Total RNA was extracted from formalin fixed paraffin embedded (FFPE) intraocular ME (n=7) and from age matched ciliary body controls (n=8). The clinical history and phenotype was recorded. MiRNA profiles were determined using the Affymetrix GeneChip miRNA Arrays analyzed using expression console 1.3 software. Validation of significantly dysregulated miRNA was confirmed by quantitative real-time PCR. The web-based DNA Intelligent Analysis (DIANA)-miRPath v2.0 was used to perform enrichment analysis of differentially expressed (DE) miRNA gene targets in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. RESULTS: The pathologic evaluation revealed one benign (benign non-teratoid, n=1) and six malignant tumors (malignant teratoid, n=2; malignant non-teratoid, n = 4). A total of 88 miRNAs were upregulated and 43 miRNAs were downregulated significantly (P<0.05) in the tumor specimens. Many of these significantly dysregulated miRNAs were known to play various roles in carcinogenesis and tumor behavior. RT-PCR validated three significantly upregulated miRNAs and three significantly downregulated miRNAs namely miR-217, miR-216a, miR-216b, miR-146a, miR-509-3p and miR-211. Many DE miRNAs that were significant in ME tumors showed dysregulation in retinoblastoma, glioblastoma, and precursor, normal and reactive human cartilage. Enriched pathway analysis suggested a significant association of upregulated miRNAs with 15 pathways involved in prion disease and several types of cancer. The pathways involving significantly downregulated miRNAs included the toll-like receptor (TLR) (p<4.36E-16) and Nuclear Factor kappa B (NF-κB) signaling pathways (p<9.00E-06). CONCLUSIONS: We report significantly dysregulated miRNAs in intraocular ME tumors, which exhibited abnormal profiles in other cancers as well such as retinoblastoma and glioblastoma. Pathway analysis of all dysregulated miRNAs shared commonalities with other cancer pathways.

Attitudes of Saudi parents with a deaf child towards prenatal diagnosis and termination of pregnancy.

OBJECTIVE: The aim of this study was to assess the attitudes of Muslim parents from Saudi Arabia with a deaf child towards prenatal diagnosis (PND) and termination of pregnancy (TOP) for deafness and 29 other genetic and medical conditions. METHODS: A questionnaire mainly focused on parent's attitude toward PND and TOP for 30 different hypothetical scenarios for a series of genetic, non-genetic and non-medical conditions was completed by 70 Saudi parents with a deaf child. The results were compared and scored, and parents' comments were noted. RESULTS: The attitude for PND was favorable (81.4%) and was influenced by the severity of the condition among men. Among women, it was influenced by cultural considerations. For TOP, average acceptance rate (25.2%) was lower than for PND. Attitudes toward TOP were fairly similar for men and women, as both groups would consider TOP for Alzheimer disease, cleft lip and palate, and cystic fibrosis. In addition, women also ranked high deafness and thalassemia for consideration of TOP. Acceptance for TOP was not influenced by gender, income, education level, number of children, or partner attending clinic. CONCLUSION: In the Saudi society, cultural consideration influences attitudes towards PND and TOP rather than the severity of the condition.

Xq26.3 microdeletion in a male with Wildervanck Syndrome.

BACKGROUND: Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family. MATERIALS AND METHODS: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization. RESULTS: The patient had bilateral type 1 DRS, fusion of almost the entire cervical spine, and bilateral severe sensorineural hearing loss due to bilateral cochlear dysplasia; he also had congenital heart disease requiring surgery. His parents were unrelated, and he had eight unaffected siblings. The patient had no mutation found by Sanger sequencing of HOXA1, KIF21A, SALL4, and CHN1. He had a 3kB deletion in the X-chromosome at Xq26.3 that was not found in his mother, one unaffected sibling, or 56 healthy controls of matching ethnicity. This deletion encompassed only one gene, Fibroblast Growth Factor Homologous Factor 13 (FGF13), which encodes a 216-amino acid protein that acts intracellularly in neurons throughout brain development. CONCLUSIONS: Analysis of this patient's phenotype and genotype open the possibility that X-chromosome deletions may be a cause of WS with larger deletions being lethal to males and that FGF13 mutations may be a cause of WS.

Partial chromosome 7 duplication with a phenotype mimicking the HOXA1 spectrum disorder.

PURPOSE: To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retraction syndrome and hearing impairment resulting in a phenotype resembling the HOXA1 spectrum disorder. METHODS: Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH). RESULTS: The proband had bilateral Duane retraction syndrome (DRS) with severe hearing loss bilaterally and an absent right vertebral artery, mimicking the major features of the Bosley-Salih-Alorainy variant of the HOXA1 spectrum. However, he also had developmental delay, mild mental retardation, and seizures. His parents were not related, but his father had milder sensorineural hearing loss bilaterally, and two paternal uncles and a paternal cousin had seizures. Neuroimaging revealed moderate maldevelopment of inner ear bony anatomy bilaterally. HOXA1 sequencing was normal, but arrayCGH revealed a small partial duplication of chromosome 7 encompassing only the PTPRN2 gene (protein tyrosine phosphatase, receptor type, N polypeptide 2) that was not present in his parents, an unaffected brother, or 53 normal ethnically-matched individuals. CONCLUSIONS: PTPRN2 is not yet linked to a genetic syndrome, although its expression has been identified in the adult human brain, in certain tumors, and in association with type 1 diabetes mellitus. The phenotype of this patient is strikingly similar to, but not identical to, that of the HOXA1 spectrum disorder. The findings in this patient raise the possibility that PTPRN2 may be active during early development of the human brainstem and that its overexpression may cause bilateral DRS with hearing loss as occurs in patients with homozygous HOXA1 mutations.

Genetic analysis of Indian subjects with clinical features of possible type IIa hypercholesterolemia.

We performed genetic analysis in 55 patients with clinical features of possible type IIa hypercholesterolemia and 76 normolipemic healthy subjects for mutations and polymorphisms in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B-100 (APOB), apolipoprotein E (APOE), and hepatic lipase (LIPC) genes to elucidate the important genetic factors that can influence cholesterol levels in our population. None of the subjects showed mutations in part of exon 26 of the APOB gene, whereas two class 5 mutations were identified in exon 9 of the LDLR gene. First, an E387K mutation was observed in a Gujarati family in which both the parents were heterozygous for the mutation. Second, a L393R mutation was observed in a 38-year-old female. We found no correlation between LIPC -514C/T genotypes and cholesterol levels whereas the apoepsilon4 allele frequency was significantly higher in cases and the apoE4 genotype was found to influence total cholesterol levels.

MEN1 935-1G>C splicing mutation in an Indian patient with multiple endocrine neoplasia type 1.

BACKGROUND AND OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized mainly by multiple tumors involving parathyroid, pancreatic, and pituitary glands. To date, there have been no genetic studies reported on MEN1 in the Indian population. In order to begin to establish molecular diagnosis to improve the management of MEN1 in India, we performed a molecular analysis of the MEN1 gene in a patient of Indian origin. METHODS: Molecular analysis of the MEN1 gene was performed to identify mutations in an Indian patient previously diagnosed with sporadic MEN1. All the 10 exons of the MEN1 gene were amplified using the polymerase chain reaction and screened by direct DNA sequencing. RESULTS: The DNA sequencing results revealed the presence of an intronic, heterozygous, splicing mutation 935-1G>C in intron 5 of the MEN1 gene. CONCLUSION: This study provides the first data on genetic analysis of MEN1 in Indian patients.

Lipid, lipoprotein, apolipoprotein and lipoprotein(a) levels: reference intervals in a healthy Indian population.

The role of lipids, lipoproteins and lipoprotein(a) [Lp(a)] in coronary artery disease (CAD) is known but the role of major apolipoproteins (apos) other than apo A-I and apo B remains unclear. In this study, using immunoturbidimetry we have estimated serum levels of total cholesterol, HDL-C, LDL-C, triglyceride, LDL-apoB and all major apos; A-I, A-II, B, C-II, C-III and E, in 751 healthy Indian subjects (470 men and 281 women, age 25-65 years), determined their percentiles, and established reference intervals. The effects of age, smoking and alcohol on all these analytes were also evaluated. This is the first study to provide reference intervals for all apos, in both sexes from a general population. The percentiles and the reference intervals have clinical relevance and will be useful in assessing the risk of CAD in patients with hyperlipidemia and other diseases.

Application of multiplex ARMS and SSCP/HD analysis in molecular diagnosis of cystic fibrosis in Indian patients.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The most severe, DeltaF508, mutation accounts for nearly 70% of CF cases worldwide. Besides DeltaF508, there are other point mutations, namely G542X, G551D, R553X, N1303K, and 621+1(G-->T), which are common among Caucasians. Additionally, a polyT polymorphism in intron 8 is also involved in the pathogenesis of CF. However, neither the prevalence nor the types of mutations causing CF in India are known. In this study, we aimed at estimating the frequency of the above common mutations and polymorphism in clinically suspected CF cases. We also carried out partial analysis of the CFTR gene, limited to exons 10 and 11, to identify other variations in these exons. METHODS: The multiplex amplification refractory mutation system (ARMS) test was applied for rapid simultaneous analysis of six most common CF mutations, in 100 normal and 39 elevated sweat chloride cases. The scanning of exons 10 and 11 was carried out by single-stranded conformation polymorphism/heteroduplex (SSCP/HD) analysis, followed by DNA sequencing in 50 normal and 37 elevated sweat chloride cases. A single ARMS-polymerase chain reaction assay was used to distinguish the 5T, 7T, and 9T alleles in 100 normal and 33 elevated sweat chloride cases. RESULTS: The multiplex ARMS analysis identified the DeltaF508 mutation at an allele frequency of 24% in Indian CF cases. However, the other predominant CF mutations were found to be absent. The 7T polyT variant was observed to be the most common allele, followed by the 9T, and 5T, which was the lowest. The DeltaF508 mutation was observed in all instances with the 9T variant. The SSCP/HD and DNA sequencing additionally revealed a known polymorphism (M470V, exon 10) and a known mutation [1525-1(G-->A), intron 9]. The 1525-1(G-->A) mutation, observed in a single 4-year-old male, is predicted to code for a class II defective CFTR protein. CONCLUSION: The findings of this study suggest a difference in relative frequencies and spectrum of CFTR mutations in Indian CF cases. A larger screening study of the entire CFTR gene in clinically well defined CF cases is required to delineate common mutations in the CFTR gene and enable molecular diagnosis of CF in India.

Gene polymorphism and coronary risk factors in Indian population.

Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in molecular cardiology have revealed a number of single nucleotide polymorphisms associated with atherosclerosis. In this review, gene polymorphisms that have been associated with coronary diseases among Indians are discussed. Topics include the genes involved in hyperlipidemia, hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor (LDLR) gene resulting in familial hypercholesterolemia have strong association with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo) B-100 and E genes have been associated with variation in lipid and lipoprotein levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a feature now also common among Asian Indians. Angiotensin-converting enzyme-deletion (DD) polymorphism has been shown to influence beta-blocker therapy in heart failure. Mutations in methylenetetrahydrofolate reductase (C667T), cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the genetics of atherosclerosis continues to evolve, these factors along with the newer emerging factors may become a part of the routine assessment, aiding prediction of future coronary events.