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Mitochondria play a critical role in the generation of metabolic energy in the form of ATP. Tissues and organs that are highly dependent on aerobic metabolism are involved in mitochondrial disorders including nonsyndromic hearing loss (NSHL). Seven pathogenic variants leading to NSHL have so far been reported on two mitochondrial genes: MT-RNR1 encoding 12SrRNA and MT-TS1 encoding tRNA for Ser((UCN)) . We screened 729 prelingual NSHL subjects to determine the prevalence of MT-RNR1 variants at position m.961, m.1555A>G and m.1494C>T, and MT-TS1 m.7445A>G, m.7472insC m.7510T>C and m.7511T>C variants. Mitochondrial pathogenic variants were found in eight probands (1.1%). Five of them were found to have the m.1555A>G variant, two others had m.7472insC and one proband had m.7444G>A. The extended relatives of these probands showed variable degrees of hearing loss and age at onset. This study shows that mitochondrial pathogenic alleles contribute to about 1% prelingual hearing loss. This study will henceforth provide the reference for the prevalence of mitochondrial pathogenic alleles in the South Indian population, which to date has not been estimated. The m.1555A>G variant is a primary predisposing genetic factor for the development of hearing loss. Our study strongly suggests that mitochondrial genotyping should be considered for all hearing impaired individuals and particularly in families where transmission is compatible with maternal inheritance, after ruling out the most common variants.

mutations to nonsyndromic hearing lossin a special cohort of assortatively mating HI individualsand their families from the state of Kerala in southern India.A comprehensive approach of screening the extended fam-ilies of the HI mates for studying the mutation transmis-sion pattern was also attempted. Eight such families werescreened for the presence of

Summary Hearing loss is the most common sensory disorder and is genetically heterogeneous. Apart from nuclear gene mutations, a number of inherited mitochondrial mutations have also been implicated. The m.1555A>G mutation in the mitochondrial MT-RNR1 gene is reported as the most common mutation causing nonsyndromic hearing loss in various ethnic populations. We report here for the first time the clinical, genetic and molecular characterisation of a single large five-generational Tamil-speaking South Indian family with maternally inherited nonsyndromic postlingual hearing loss. Molecular analysis led to identification of m.1555A>G in 28 maternal relatives with variable degree of phenotypic expression. The penetrance of hearing loss among the maternal relatives in this family was 55%. Sequence analysis of the complete mitochondrial genome in 36 members of this pedigree identified 25 known variants and one novel variant co-transmitted along with m.1555A>G mutation. The mtDNA haplotype analysis revealed that the maternal relatives carry the R*T2 haplotype similar to Europeans and South Asians. Sequencing of the coding exon of GJB2 nuclear gene did not show any pathogenic mutations. The results suggest that other nuclear or environmental modifying factors could have played a role in the differential expression of mutation m.1555A>G in postlingual hearing loss in this family.

KEYWORDS Hypertension. Angiotensinogen. Gene Polymorphism. M235T. T174M. Renin-angiotensin-system ABSTRACT Hypertension is complex multi factorial disease; the development and progression of hypertension varies from population to population. The T174M and M235T polymorphisms of the AGT gene have been reported to be associated with essential hypertension in many populations. The researchers analyzed the possible association of T174M and M235T polymorphisms of AGT gene in essential hypertension patients (n=254) of Tamil Nadu, India along with equal number of age and sex matched control subjects. Results revealed that 235T mutation is an independent risk factor for essential hypertension in this study group (RR = 2.52; χ2 = 39.32; CI = 1.89-3.371). It is a risk factor for both younger (RR = 2.72; χ 2 = 16.39; CI = 1.689-4.380) and older age (RR = 2.48; χ 2 = 16.53; CI = 1.60-3.839) groups. 174M is a more potent risk allele for younger onset (RR = 1.54; χ2 = 3.97; CI = 1.01-2.34) of hypertensive patients than in the older (RR = 1.09; χ2 = 0.14; CI = 1.42-1.67) essential hypertensive patients. Further both T174M and M235T polymorphisms were observed to be high risk factors in females than in males. Our finding suggested that both polymorphisms (M235T and T174M) are independent risk factors for essential hypertension while homozygous TT235 has greater effect than the MM174 mutation.

Urban atmosphere contains a variety of chemicals which are potentially genotoxic and carcinogenic. An increased risk of lung cancer in certain occupational groups is due to exposure to traffic-related pollution. Few reports are available in India on the genetic damage caused by exposure to automobile exhaust pollution on traffic policemen. Therefore, the present work was undertaken to study the genetic risk assessment in traffic policemen of Chennai city by Sister Chromatid Exchange Analysis. The study subjects consisted of 56 traffic policemen who worked in high density traffic areas of Chennai city and 25 office workers unexposed to traffic as controls were used. Sister chromatid exchanges (SCEs) were analyzed in peripheral blood lymphocytes drawn from both subjects. The results expressed as mean SCEs/cell was found significantly ( p

Primary amenorrhea refers to absence of spontaneous menarche even after the age of 16 while in secondary amenorrhea, the condition follows a period of normal menstruation. Cytogenetic data in cases with primary (n=852) (PA) or secondary (n=127) amenorrhea (SA) investigated at the Department of Genetics, Dr. A.L. Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, during the 25-year period 1979 to 2004 was reviewed. Routine GTG-band analysis of metaphases from peripheral blood leucocytes revealed the incidence of chromosomal abnormalities in individuals with PA and SA to be 25.82% and 7.09% respectively. In addition to numerical abnormalities, the various structural aberrations of the X chromosome encountered were deletions, isochromosome for the long arm, translocations and ring chromosomes. Ascertainment of the karyotype aided in confirmation of the provisional diagnosis, a better phenotype-genotype correlation to understand clinical heterogeneity and in genetic counseling

Mentha spicata is a well-known spice that has a variety of biological properties and is abundantly available throughout the world. This study was designed to investigate the superoxide radical scavenging and antibacterial properties of different fractions (hexane, chloroform, ethyl acetate, and aqueous) of the ethanol extract of Mentha spicata. In addition, xanthine oxidase generated uric acid inhibition, reducing potential and iron chelating activity, also was investigated. Ethyl acetate fraction exhibited the highest (≤84%) superoxide radical scavenging and inhibition of uric acid formation at 40 μg/ml compared with the standard quercetin (≤81%) at 30 μg/ml. The highest reducing potential also is observed in ethyl acetate and aqueous fractions, which were comparable to the reducing potential of quercetin and ascorbic acid. Iron chelating activity of solvent fractions was found to be better than standard of EDTA (79% at 3 mg/ml). In addition, all fractions showed effective antibacterial activity against five human pathogenic bacteria among the ten samples used. However, aqueous fraction showed maximum growth inhibition zone (≤36 mm diameter at 6 μg/per disc) against Shigella boydii. Hence, we conclude that the ethyl acetate and aqueous fractions of ethanol extract of Mentha spicata exhibited higher superoxide radical scavenging and antibacterial activities.

Hypertension is a complex multifactorial disease, which affects 10-30 % of the world population. The genetic factors of the hypertension vary from population to population. Renin angiotensin system (RAS) genes play a key role in salt-water homeostasis and blood pressure regulation. The genetic polymorphisms of the angiotensinogen (AGT) gene are associated with hypertension in different populations and some of these polymorphisms (G-6A and M235T) have a significant role in the human evolution and selection fitness. The present study was carried out to find out the role of the core promoter variants {-20(A-20C),-18(T-18C) and -6(G-6A)} in causing hypertension in rural and urban hypertensive patients of Tamilnadu. Methods: A total of 254 hypertensive and 254 normotensive subjects were screened using PCR-SSCP and RFLP methods followed by DNA sequencing. The sequences were analysed by BLAST. Results: The genotype frequencies of A-20C (AA,AC,CC), C-18T (CC,CT, TT) and -6G(AA,AG,GG) in patients/controls respectively were 63.0,33.0,4.0/67.5,28.5,4.0; 99.0,1.0,0.0/99.6,0.4,0.0 and 83.0,17.0,0.0/ 81.6,18.5,0.0 Observation and Conclusion: None of these promoter variants were significantly associated with hypertension. The A allele of G-6A polymorphism was found in a high frequency in patients and controls (about 91%) which correlates with frequencies observed in African and Asian ethnic populations (80-95%).

Alu insertion/deletion polymorphisms (Alu ACE, Alu PV92 and Alu APO) were studied in three Telugu - speaking immigrants of Tamil Nadu, to understand their affinities with Andhra Pradesh population. Gene frequencies and average heterozygosity were calculated. All the three loci are polymorphic in nature and showed high levels of heterozygosity. Phylogenetic analysis of the present data with the available data of two Tamil Nadu caste population and Yadavar of Andhra Pradesh revealed that all the three immigrant populations did not show closeness with the Andhra Yadavar.

Genomic affinity based on eight human - specific polymorphic insertion/ deletion loci was studied in an early immigrant population, Thevar group, of Tamil Nadu, South India. They are traditionally agriculturists, culturally homogenous and endogamous. The seven Alu elements (Alu APO, Alu CD4, Alu PV92, Alu FXIIIB, Alu ACE, Alu PLAT, Alu D1) and one nuclear insertion of mitochondrial DNA segment (mtNUC) were analyzed for all the DNA samples. All these loci showed high levels of polymorphism in caste populations of Tamil Nadu, thereby reflecting their common ancestry. The significant greater inter-individual variation and the moderate population differentiation probably indicate genetic closeness of these populations. The present study populations were also compared with six other caste populations of Tamil Nadu for which the data were available. Phylogenetic analysis of these populations broadly corresponds to their known ethno-historical affinities.

Ezrin, radixin, and moesin are paralogous proteins that make up the ERM family and function as cross-linkers between integral membrane proteins and actin filaments of the cytoskeleton. In the mouse, a null allele of Rdx encoding radixin is associated with hearing loss as a result of the degeneration of inner ear hair cells as well as with hyperbilirubinemia due to hepatocyte dysfunction. Two mutant alleles of RDX [c.1732G>A (p.D578N) and c.1404_1405insG (p.A469fsX487)] segregating in two consanguineous Pakistani families are associated with neurosensory hearing loss. Both of these mutant alleles are predicted to affect the actin-binding motif of radixin. Sequence analysis of RDX in the DNA samples from the original DFNB24 family revealed a c.463C>T transition substitution that is predicted to truncate the protein in the FERM domain (F for 4.1, E for ezrin, R for radixin, and M for moesin) (p.Q155X). We also report a more complete gene and protein structure of RDX, including four additional exons and five new isoforms of RDX that are expressed in human retina and inner ear. Further, high-resolution confocal microscopy in mouse inner ear demonstrates that radixin is expressed along the length of stereocilia of hair cells from both the organ of Corti and the vestibular system. Hum Mutat 28(5), 417–423, 2007. Published 2007 Wiley-Liss, Inc.

Mitochondria play a critical role in the generation of metabolic energy in the form of ATP. Tissues and organs that are highly dependent on aerobic metabolism are involved in mitochondrial disorders including nonsyndromic hearing loss (NSHL). Seven pathogenic variants leading to NSHL have so far been reported on two mitochondrial genes: MT-RNR1 encoding 12SrRNA and MT-TS1 encoding tRNA for Ser((UCN)) . We screened 729 prelingual NSHL subjects to determine the prevalence of MT-RNR1 variants at position m.961, m.1555AG and m.1494CT, and MT-TS1 m.7445AG, m.7472insC m.7510TC and m.7511TC variants. Mitochondrial pathogenic variants were found in eight probands (1.1%). Five of them were found to have the m.1555AG variant, two others had m.7472insC and one proband had m.7444GA. The extended relatives of these probands showed variable degrees of hearing loss and age at onset. This study shows that mitochondrial pathogenic alleles contribute to about 1% prelingual hearing loss. This study will henceforth provide the reference for the prevalence of mitochondrial pathogenic alleles in the South Indian population, which to date has not been estimated. The m.1555AG variant is a primary predisposing genetic factor for the development of hearing loss. Our study strongly suggests that mitochondrial genotyping should be considered for all hearing impaired individuals and particularly in families where transmission is compatible with maternal inheritance, after ruling out the most common variants.

KEYWORDS Down syndrome; mosaicism; Robertsonian translocation; XYY males ABSTRACT Double aneuploidy involving XYY and trisomy 21 is rare. XYY/XY mosaicism has been described in only a single Down syndrome patient. The Robertsonian translocation t(13;21) is also rare among these individuals. We report for the first time the occurrence of t(13;21) in a mosaic XYY Down male. Analysis of GTG-banded metaphases revealed the karyotype of the propositus to be mos 47,XYY,der(13;21)(q10;q10),+21/ 46,XY,der(13;21),+21. Both his father and paternal grandfather were found to be carriers for the translocation. This 10-month-old child who presented with typical features of Down syndrome, developed leukemia and died at the age of 2¼ years.

Although considerable cultural impact on social hierarchy and language in South Asia is attributable to the arrival of nomadic Central Asian pastoralists, genetic data (mitochondrial and Y chromosomal) have yielded dramatically conflicting inferences on the genetic origins of tribes and castes of South Asia. We sought to resolve this conflict, using high-resolution data on 69 informative Y-chromosome binary markers and 10 microsatellite markers from a large set of geographically, socially, and linguistically representative ethnic groups of South Asia. We found that the influence of Central Asia on the pre-existing gene pool was minor. The ages of accumulated microsatellite variation in the majority of Indian haplogroups exceed 10,000-15,000 years, which attests to the antiquity of regional differentiation. Therefore, our data do not support models that invoke a pronounced recent genetic input from Central Asia to explain the observed genetic variation in South Asia. R1a1 and R2 haplogroups indicate demographic complexity that is inconsistent with a recent single history. Associated microsatellite analyses of the high-frequency R1a1 haplogroup chromosomes indicate independent recent histories of the Indus Valley and the peninsular Indian region. Our data are also more consistent with a peninsular origin of Dravidian speakers than a source with proximity to the Indus and with significant genetic input resulting from demic diffusion associated with agriculture. Our results underscore the importance of marker ascertainment for distinguishing phylogenetic terminal branches from basal nodes when attributing ancestral composition and temporality to either indigenous or exogenous sources. Our reappraisal indicates that pre-Holocene and Holocene-era--not Indo-European--expansions have shaped the distinctive South Asian Y-chromosome landscape.

The genotoxic potential of anti-tumor drugs limits their efficacy in the treatment of cancers. Since ancient times, saffron (dried stigmas of Crocus sativus L.) has been used as a spice and medicinal herb. Saffron is a rich source of carotenoids and is known for its anti-cancer and antitumor properties. The present study was designed to ascertain the chemoprotective potential of saffron against the genotoxicity of three well-known anti-tumor drugs-cisplatin (CIS), cyclophosphamide (CPH) and mitomycin C (MMC)-using comet assay. Three doses of saffron (20, 40 and 80 mg/kg b.w.) were orally administered to mice for five consecutive days prior to the administration of anti-tumor drugs under investigation. Pre-treatment with saffron significantly inhibited anti-tumor drugs induced cellular DNA damage (strand breaks) as revealed by decreased comet tail length, tail moment and percent DNA in the tail. These findings, together with our previous results, suggest a potential role for saffron as an anti-genotoxic, anti-oxidant and chemopreventive agent and could be used as an adjuvant in chemotherapeutic applications.

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies.

We previously mapped the DFNB17 locus to a 3-4 cM interval on human chromosome 7q31 in a large consanguineous Indian family with congenital profound sensorineural hearing loss. To further refine this interval, 30 new highly polymorphic markers and 8 SNPs were analyzed against the pedigree. Re-analysis in the original DFNB 17 family and additional data from a second unrelated consanguineous family with congenital deafness found to map to the interval, limited the area of shared homozygosity-by-descent (HBD) to approximately 4 megabase (Mb) between markers D7S2453 and D7S525. Nineteen known genes and over 20 other cDNAs have been identified in the refined DFNB 17 interval, including the SLC26A4 gene. We have analyzed 4 other cochlear-expressed genes that map to the DFNB17 interval as candidate genes. Analysis of coding and splice site regions of these cochlear expressed genes did not reveal any disease causing mutations. Further study of other candidate genes is currently underway.

The modifying effects of the aqueous extract of saffron (dried stigmas of Crocus sativus Linn.) on cisplatin (CIS), cyclophosphamide (CPH), mitomycin-C (MMC) and urethane (URE) induced alterations in lipid peroxidation and antioxidant status were investigated in Swiss albino mice. Three doses of saffron (20, 40 and 80 mg/kg body weight) were orally administered to mice for 5 consecutive days prior to administration of genotoxins. A significant reduction in the extent of lipid peroxidation with a concomitant increase in the liver enzymatic (SOD, CAT, GST, GPx) and non-enzymatic antioxidants (reduced glutathione) were observed in saffron pretreated animals compared with the genotoxins alone treated animals. However, the modulatory effects were not always dose dependent. Our data suggest that saffron may exert its chemopreventive effects by modulation of lipid peroxidation, antioxidants and detoxification systems.

We have identified five different homozygous recessive mutations in a novel gene, TMIE (transmembrane inner ear expressed gene), in affected members of consanguineous families segregating severe-to-profound prelingual deafness, consistent with linkage to DFNB6. The mutations include an insertion, a deletion, and three missense mutations, and they indicate that loss of function of TMIE causes hearing loss in humans. TMIE encodes a protein with 156 amino acids and exhibits no significant nucleotide or deduced amino acid sequence similarity to any other gene.

Mutations in the autosomal genes TMPRSS3, TMC1, USHIC, CDH23 and TMIE are known to cause hereditary hearing loss. To study the contribution of these genes to autosomal recessive, non-syndromic hearing loss (ARNSHL) in India, we examined 374 families with the disorder to identify potential mutations. We found four mutations in TMPRSS3, eight in TMC1, ten in USHIC, eight in CDH23 and three in TMIE. Of the 33 potentially pathogenic variants identified in these genes, 23 were new and the remaining have been previously reported. Collectively, mutations in these five genes contribute to about one-tenth of ARNSHL among the families examined. New mutations detected in this study extend the allelic heterogeneity of the genes and provide several additional variants for structure-function correlation studies. These findings have implications for early DNA-based detection of deafness and genetic counseling of affected families in the Indian subcontinent.

The genotoxic and antigenotoxic potential of the ethanolic extract of Hemidesmus indicus roots were evaluated in cultured human lymphocytes using cisplatin as the positive mutagen.Cytogenetic damage and cytotoxicity were determined in cells exposed to different doses of the extract, ranging from 2 to 32 microg/ml of culture medium, either alone or together with cisplatin.There was a significant reduction in cisplatin-induced frequencies of sister chromatid exchanges, chromosome aberrations and micronucleated binucleate cells at the lower concentrations of 4 and 8 microg/ml (P0.05). However, the extract by itself reduced the proliferative rate index, mitotic index and cytokinesis-block proliferative index (P0.05). Further, a significant increase in the percentage of chromosome aberrations was noticed at the higher concentrations.Hemidesmus indicus root extract possesses significant genoprotective effect at the lower concentrations although it is cytotoxic and probably genotoxic at higher doses.

The combined DFNB7–DFNB11 deafness locus maps to chromosome 9q13–q21 between markers D9S1806 and D9S769. We have determined the cDNA sequence and genomic structure of a novel gene, TMEM2 , that maps to this interval and is expressed in the cochlea. The mouse orthologue of this gene ( Tmem2 ) maps to the murine dn (deafness) locus on mouse chromosome 19. Screens for transmembrane helices reveal the presence of at least one putative transmembrane domain in the TMEM2 protein. To determine whether mutations in TMEM2 cause hearing loss at the DFNB7–DFNB11 locus, we screened the coding region of this gene in DFNB7–DFNB11 affected families by direct sequencing. All DNA variants that segregated with the deafness and changed the predicted amino acid sequence of TMEM2 were common polymorphisms, as demonstrated by allele-specific amplification of pooled control DNA. Northern blot analysis showed no difference in transcript size or expression level of Tmem2 in dn/dn and control mice. The intragenic polymorphisms in TMEM2 represent a novel centromeric boundary for the DFNB7–DFNB11 interval.

The DFNB7/11 locus for autosomal recessive non-syndromic hearing loss (ARNSHL) has been mapped to an approx. 1.5 Mb interval on human chromosome 9q13-q21. We have determined the cDNA sequence and genomic structure of a novel cochlear-expressed gene, ZNF216 , that maps to the DFNB7/11 interval. The mouse orthologue of this gene maps to the murine dn (deafness) locus on mouse chromosome 19. The ZNF216 gene is highly conserved between human and mouse, and contains two regions that show homology to the putative zinc finger domains of other proteins. To determine if mutations in ZNF216 might be the cause of hearing loss at the DFNB7/11 locus, we screened the coding region of this gene in DFNB7/11 families by direct sequencing. No potential disease-causing mutations were found. In addition, Northern blot analysis showed no difference in ZNF216 transcript size or abundance between dn and control mice. These data suggest that the ZNF216 gene is unlikely to be responsible for hearing loss at the DFNB7/11 and dn loci.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families.

Hereditary hearing impairment affects approximately 0.05% of all children born in the United States. It is most commonly autosomal recessive, nonsyndromic, and monogenic [autosomal recessive nonsyndromic hearing loss (ARNSHL)]. Although the number of disease loci is not known, some estimates exceed 100. Using a strategy of homozygosity mapping to localize ARNSHL genes by screening consanguineous families for chromosomal regions that are homozygous by descent, we have mapped several genes in multiplex, nuclear, consanguineous families in Tamil Nadu, India. From the mean frequency of the ARNSHL genes in this population, the total number of disease genes is estimated to be 57.

Mutations in the Cx26 gene have been shown to cause autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB1 locus on chromosome 13q12. Using direct sequencing, we screened the Cx26 coding region of affected and nonaffected members from seven ARNSHL families either linked to the DFNB1 locus or in which the ARNSHL phenotype cosegregated with markers from chromosome 13q12. Cx26 mutations were found in six of the seven families and included two previously described mutations (W24X and W77X) and two novel Cx26 mutations: a single base pair deletion of nucleotide 35 resulting in a frameshift and a C-to-T substitution at nucleotide 370 resulting in a premature stop codon (Q124X). We have developed and optimized allele-specific PCR primers for each of the four mutations to rapidly determine carrier and noncarrier status within families. We also have developed a single stranded conformational polymorphism (SSCP) assay which covers the entire Cx26 coding region. This assay can be used to screen individuals with nonsyndromic hearing loss for mutations in the CX26 gene.

Pendred syndrome is an autosomal recessive disorder characterized by early childhood deafness and goiter. A century after its recognition as a syndrome by Vaughan Pendred, the disease gene ( PDS ) was mapped to chromosome 7q22-q31.1 and, recently, found to encode a putative sulfate transporter. We performed mutation analysis of the PDS gene in patients from 14 Pendred families originating from seven countries and identified all mutations. The mutations include three single base deletions, one splice site mutation and 10 missense mutations. One missense mutation (L236P) was found in a homozygous state in two consanguineous families and in a heterozygous state in five additional non-consanguineous families. Another missense mutation (T416P) was found in a homozygous state in one family and in a heterozygous state in four families. Pendred patients in three non-consanguineous families were shown to be compound heterozygotes for L236P and T416P. In total, one or both of these mutations were found in nine of the 14 families analyzed. The identification of two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of prelingual inherited hearing impairment. A small consanguineous family with this disorder was ascertained through the Institute of Basic Medical Sciences in Madras, India. Conditions such as rubella, prematurity, drug use during pregnancy, perinatal trauma, and meningitis were eliminated by history. Audiometry was performed to confirm severe-to-profound hearing impairment in affected persons. After excluding linkage to known DFNB genes, two genomic DNA pools, one from the affected persons and the other from their non-affected siblings and the parents, were used to screen 165 polymorphic markers evenly spaced across the autosomal human genome. Two regions showing homozygosity-by-descent in the affected siblings were identified on chromosomes 3q21.3-q25.2 and 19p13.3-p13.1, identifying one (or possibly both) as the site of a novel ARNSHL gene. (C) 1997 Wiley-Liss, Inc.

DFNB7 and DFNB11, two loci for autosomal recessive nonsyndromic hearing loss (ARNSHL), have been mapped to chromosome 9q13–21 in separate consanguineous families. Using a radiation hybrid map, we have determined the correct marker order in the DFNB7/11 region and have demonstrated that theDFNB11 locus resides within a redefined DFNB7interval. The gene(s) responsible for ARNSHL at these loci resides within an ∼1 cM interval bounded by markers D9S1806(centromeric) and D9S769 (telomeric). A recently discovered Indian family confirms the new telomeric boundary. To assist in the identification and cloning of candidate genes, YAC and PAC contigs were constructed. A total of 19 YAC and 23 PAC clones were utilized to span the affected region and ensure double coverage throughout. Twenty-two previously published STSs and 21 new STSs were used to determine marker order and confirm the integrity of the contig. Using a positional cloning strategy we have identified three cochlear expressed genes that map to the DFNB7/11 interval.

Hearing loss is the most common sensory disorder and is genetically heterogeneous. Apart from nuclear gene mutations, a number of inherited mitochondrial mutations have also been implicated. The m.1555AG mutation in the mitochondrial MT-RNR1 gene is reported as the most common mutation causing nonsyndromic hearing loss in various ethnic populations. We report here for the first time the clinical, genetic and molecular characterisation of a single large five-generational Tamil-speaking South Indian family with maternally inherited nonsyndromic postlingual hearing loss. Molecular analysis led to identification of m.1555AG in 28 maternal relatives with variable degree of phenotypic expression. The penetrance of hearing loss among the maternal relatives in this family was 55%. Sequence analysis of the complete mitochondrial genome in 36 members of this pedigree identified 25 known variants and one novel variant co-transmitted along with m.1555AG mutation. The mtDNA haplotype analysis revealed that the maternal relatives carry the R*T2 haplotype similar to Europeans and South Asians. Sequencing of the coding exon of GJB2 nuclear gene did not show any pathogenic mutations. The results suggest that other nuclear or environmental modifying factors could have played a role in the differential expression of mutation m.1555AG in postlingual hearing loss in this family.

The association of Turner syndrome (TS) with congenital cardio vascular malformations is well established. Bicuspid aortic valve and coarctation of aorta have been associated most commonly with Turner syndrome. There are also rare reports of atrial septal defect and aortic aneurysm with Turner syndrome. We report a uncommon case of transposition of great arteries (TGA) associated with turner syndrome (45, X, 16qh+).

A locus for recessive neurosensory nonsyndromic hearing impairment maps to chromosome 9q13-q21 in two regionally separate consanguineous families from India. Each family demonstrates a LOD score greater than 4.5 to this region. D9S15, tightly linked to the Friedreich's ataxia locus, a region that has been defined with over 1 Mb of YAC contig information and several expressed sequences, is one of the flanking markers. In mice, the deafness (dn) locus maps to mouse chromosome 19 and flanking loci are syntenic to human chromosome 9q11-q21. The dn mouse is a potential model for the hearing impairment found in both these families.

With the etiology being unclear till date, a combination of age, genetic and environmental factors are known to play a significant role in the pathogenesis of Parkinson's disease. Mutations in PARK2 gene have been implicated to cause autosomal recessive early onset PD. We analyzed the 12 coding exons of PARK2 gene in 16 early onset PD patients of South Indian ethnicity. PARK2 mutations were present in 68% of the early onset cases. We report the presence of four PARK2 sequence variants c.1239G>C, c.171+25T>C, c.202A>G, c.601G>A, and a novel insertion mutation, c.798_799insA in the exon 7 of PARK2 gene. These results suggest that mutations in PARK2 gene may be a common cause of PD among South Indian early onset patients.

We analysed the genetic structure of ≈ 1000 samples representing 27 ethnic groups settled in Tamil Nadu, south India, derived from two linguistic families (Dravidians and Indo-Europeans) representing four religious groups (Hinduism, Islam, Christianity and Jainism) using 11 mtDNA markers. Out of 27 ethnic groups, four are in situ populations (Anglo-Indian, Labbai Muslim, Nadar Christian and south Indian Jain) and two are migrants (Gypsy and north Indian Jain) from north India to Tamil Nadu, and 21 are native ethnic groups. Six of the markers we used were monomorphic (HaeIII663, HpaI3592, AluI5176, AluI7025, AluI13262, 9-bp deletion) and five markers were polymorphic (DdeI10394, AluI10397, HinfI12308, HincII13259 and HaeIII16517). Haplogroup frequencies, genetic affinities and admixture analysis are based on the genotype data of polymorphic markers observed in these populations. Haplogroup frequencies indicate that various ethnic groups entered Tamil Nadu during different time periods. Genetic affinities and admixture estimates revealed that the ethnic groups possessing advanced knowledge of farming cluster in a branch (C), and could be the late arrived settlers as agriculture, was introduced to this region at about 5 to 3 thousand years ago. In situ ethnic groups appear to have arisen at various times as a result of the prevailing dominant socio-cultural forces. Hierarchical Hindu caste system created many ethnic groups in the history of its existence; some of them became isolated for considerable period of time. Over all, among Tamil ethnic groups, in spite of caste systems' rigidity, built in flexibility in the system in the form of hypergamy and hypogamy had allowed maternal gene flow between them.

The antigenotoxic potential of an aqueous fraction of ethanol extract of Mentha spicata was evaluated by measuring the frequency of micronucleated polychromatic erythrocytes (MnPCEs) in mice bone marrow, using 4-nitroquinoline-1oxide (NQO) as the reference mutagen. In addition, lipid peroxidation (LPO) and antioxidant levels were also quantified with liver tissue of the same mice to assess their antioxidant potential. Swiss albino mice of either sex (25-30 g) were orally pretreated with an aqueous fraction (80, 160, and 320 mg/kg) for 5 consecutive days. NQO (7.5 mg/kg) was injected intraperitoneally after 2 hours until the final day (day 5) of treatment with aqueous fraction. Animals were sacrificed 24 hours later by cervical dislocation and processed for micronuclei and bioassays. A significant reduction (about 67%) of NQO-induced MnPCE frequency was observed at the dose of 320 mg/kg. The LPO was also suppressed effectively, with concomitant changes in both enzymatic and nonenzymatic antioxidants. The restoration level was dose dependent in LPO and glutathione-s-transferase, whereas it was dose independent in superoxide dismutase, glutathione peroxidase, catalase, and reduced glutathione. The results indicate that the aqueous fraction of M. spicata mediates their antigenotoxic effects by the modulation of LPO and antioxidant enzymes.

Background and Aims. Peroxisome proliferator activated receptor-g (PPARg) and lipoprotein lipase (LPL) genes are important in pathways of triglyceride metabolism, insulin resistance and adipogenesis. We hypothesized that polymorphisms of PPARg Pro12Ala, LPL HindIII and LPL Ser447X influence severity of coronary artery disease (CAD) in an Indian population. Methods. PPARg Pro12Ala, LPL HindIII and LPL Ser447X polymorphisms were genotyped in 414 patients with CAD and matched with 424 controls. The study subjects were inducted after standard diagnostic procedures and analyzed statistically for the association of polymorphisms with clinical characteristics. Results. We found that PPARg alleles were not associated with CAD among Indians although proline carriers had significantly higher levels of HDL-cholesterol (p 5 0.03) among CAD patients. The LPL HindIII also had no significant correlations for CAD or for any clinical characteristics. The Ser447X polymorphism (p 5 0.015) influenced lower triglyceride levels among CAD patients with significant associations (OR 5 0.66, 95% CI 0.483e0.915, p 5 0.012). This protective effect of the 447X allele was more pronounced among the CAD patients without the risk factor of diabetes (OR 5 0.60, 95% CI 0.403e0.907, p 5 0.014) along with less progression of a severe atherosclerotic disease. Conclusions. PPARg and LPL have intractable roles in pathways that lead to CAD, but their gene polymorphisms associate differently. Our results imply a significant correlation of Ser447X polymorphism and its protective effect on Indians against severity of CAD modified by the risk of diabetes, than LPL HindIII and PPARg Pro12Ala. 2010 IMSS. Published by Elsevier Inc.

Apolipoprotein C3 and apolipoprotien A5 are proteins coded from the APOA1/C3/A4/A5 gene cluster. Sst I polymorphism on apolipoprotein C3 and −1131C polymorphism of apolipoprotien A5 are key variants involved in triglyceride metabolism and cause a significant cardio-metabolic risk. Here, we have evaluated these two variants for their roles in coronary artery disease in patients of the Indian population. The apolipoprotein gene cluster variants were analysed in 416 angiographically determined coronary artery disease patients and matched 416 controls using polymerase chain reaction—restriction fragment length polymorphism. The characteristics of the study subjects were analyzed statistically for their association with the polymorphisms. The alleles were combined as haplotypes and their combined risks were evaluated. The minor allele genotypes of both apolipoprotein C3 (S2) and apolipoprotien A5 (C) had a significant risk for coronary artery disease. The S2 allele genotyped patients had a significantly increased triglyceride level (P

In a study of 530 individuals with non-syndromic, sensorineural hearing loss, we identified 18 mutations at connexin 26 (Cx26), four of which are novel (-23G>T, I33T, 377_383dupTCCGCAT, W172R) and the remaining 14 (ivs1+1G>A, M1V, 35delG, W24X, I35S, V37I, R75W, W77X, 312del14, E120del, Q124X, Y136X, R143W, R184P) being mutations previously described. To gain insight into functional consequences of these mutations, cellular localization of the mutant proteins and their ability to permit lucifer yellow transfer between cells was studied in seven of them (W24X, I33T, I35S, R75W, E120del, W172R and R184P). I35S and R184P showed impaired trafficking of the protein to the plasma membrane. I33T, R75W, E120del and W172R showed predominantly membrane localization but did not form functional gap junction channels. Surprisingly, W24X, a protein-truncating mutation, apparently permits formation of a full-length protein, perhaps due to a stop codon read-through mechanism. These results provide further evidence that Cx26 mutations affect gap junction activity by mis-regulation at multiple levels.

The present study aims to describe the genetic structure ofthe scheduled caste populations in Tamil Nadu state, and toassess their relationships with contemporary people of dif-ferent socio-economic groups of the state. We have stud-ied eight human-specific indels (insertion/deletion polymor-phisms) in DNA samples from five Tamil Nadu caste groupsusing phylogeneticand principal component analysis (PCA),and compared the data with earlier data on the three othercaste groups of the state. The results indicate that scheduledcastes are genetically heterogenous, but show closeness withother socio-economic groups of the state.The social structure of India is dominated by the Hinducaste system. Caste refers to a rigid system of ranked socialinequality with significant barriers to mobility or to intimateassociations between different strata. ‘Caste’ comes from thePortuguese word

The origin and settlement of Indian people still intrigues sci-entists studying the impact of past and modern migrationson the genetic diversity and structure of contemporary pop-ulations. About 10,000 years ago, proto-Dravidian Neolithicfarmers from Afghanistan entered the Indian subcontinent,and were later displaced southwards by a large influx ofIndo–European speakers ∼3500 years ago (Majumder

ABO and Rh blood groups in 344 filarial patients and 320 controls matched with respect to age, community and residence are reported. An excess of B and a deficiency of AB was observed among the filarial patients. The relative risks for the B and AB were 1.53 and 0.36, respectively. Only males showed clearly significant risks. The Rh(D) blood groups revealed no association with filariasis.

Spirulina fusiformis given by oral route to mice at doses of 250, 500 and 1000 mg kg(-1) significantly inhibit the genotoxicity induced by cisplatin and urethane. In addition, a significant reduction in the extent of lipid peroxidation with concomitant increase in the liver enzymatic (GPx, GST, SOD, CAT) and non-enzymatic (reduced glutathione) antioxidants were observed.

Saffron (dried stigmas of Crocus sativus L.), was evaluated in the mouse bone marrow micronucleus test for its possible protective effects against chromosomal damage induced by cisplatin (CIS), mitomycin-C (MMC) and urethane (URE). Three doses of saffron (25, 50 and 100 mg/kg body weight) were orally administered to mice for five consecutive days prior to administration of genotoxins under investigation. From the results obtained, it was evident that the administration of 50 and 100 mg saffron/kg body weight could significantly inhibit the in vivo genotoxicity of these genotoxins. However, all the three doses of saffron were effective in exerting a protective effect against urethane.

In a comparative study of sister chromatid exchanges (SCEs) in cultured lymphocytes, we evaluated the genotoxic risk in 104 male spray painters employed in repair workshops in Chennai City, India, and 50 matched healthy, unexposed controls. We found a higher frequency of SCEs among painters (3.74 +/- 0.11, mean +/- SE) than among controls (2.15 +/- 0.08), and among smoking painters (4.03 +/- 0.21) than among nonsmoking painters (3.55 +/- 0.13), with no significant difference in controls (smokers: 2.1 +/- 0.2; nonsmokers: 2.2 +/- 0.1). Alcoholism did not contribute to an increased SCE frequency. Stepwise multiple linear regression analysis on painters showed that duration of service, smoking, and alcoholism significantly affected SCE scores and explained the 14% variation observed.

Studies on the frequencies of chromosomal aberrations were carried out on 104 spray painters working in automobile body reconditioning, steel furniture making and refrigerator repainting workshops in the metro city, Chennai, of south India. Randomly selected 50 male subjects not connected with this occupation were included as controls in the study. Chromosomal analysis was carried out in 48 h lymphocyte (short duration) cultures representing the first mitotic division, on a subset of samples consisting of 50 spray painters, 20 controls and 72 h (longer duration) cultures representing the second cell division, on all subjects. Baseline frequency of chromosomal aberrations was significantly higher among painters as compared to matched controls. Smoking and alcoholism as modulating factors had no added effect on the frequency of aberrant metaphases. Stepwise multiple linear regression analysis indicated that duration of service and age were significant factors that influence the frequency of chromosomal aberrations observed.

Spirulina fusiformis was tested for its possible in vivo protective effects against cyclophosphamide (CP) and mitomycin-C (MMC) induced genotoxicity and oxidative stress in mice. Pre-treatment with S. fusiformis (250, 500 and 1000 mg kg(-1), p.o., daily for 5 days) significantly reduced the chromosomal damage and lipid peroxidation with concomitant changes in antioxidants and detoxification systems. All the three tested doses were effective in exerting a protective effect against CP and MMC.

Experiments were carried out to ascertain whether or not saffron (dried stigmas of Crocus sativus L.), a commonly used agent for flavoring and coloring food can exert modulatory effects on the in vivo genotoxicity of cisplatin (CIS), cyclophosphamide (CPH), mitomycin C (MMC) and urethane (URE). For this purpose, Swiss albino mice were pretreated for five consecutive days with three doses (20, 40 and 80 mg/kg body weight) of the aqueous extract of saffron. Genotoxic effects were assessed in the mouse bone marrow micronucleus test. The results obtained suggest that pretreatment with saffron can significantly inhibit the genotoxicity of CIS, CPH, MMC and URE. This inhibitory effect was not always dose-dependent. In addition, the hepatic glutathione S-transferase (GST) activity was assessed in the control and treated animals. No significant change in GST activity was observed after pretreatment with saffron alone. Treatment with the genotoxins alone significantly inhibited GST activity. Saffron pretreatment attenuated the inhibitory effects of the genotoxins on GST activity.