Type 2 diabetes mellitus (T2DM), by definition is a heterogeneous, multifactorial, polygenic syndrome which results from insulin receptor (IR) dysfunction. It is an outcome of oxidative stress caused by interactions of reactive metabolites (RMs) with lipids, proteins and other molecules of the human body. Production of RMs mainly superoxides (•O2−) has been found in a variety of predominating cellular enzyme systems including nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, cyclooxygenase, endothelial nitric oxide synthase (eNOS) and myeloperoxidase. The four main RM related molecular mechanisms are: increased polyol pathway flux; increased advanced glycation end-product formation; activation of protein kinase C isoforms and increased hexosamine pathway flux which have been implicated in glucose-mediated vascular damage. Superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and NOS are antioxidant enzymes involved in scavenging RMs in normal individuals. Functional polymorphisms of these antioxidant enzymes have been reported to be involved in the pathogenesis of T2DM. The low levels of antioxidant enzymes or their non-functionality results in excessive RMs which initiates stress related pathways thereby leading to IR and T2DM. An attempt has been made to review the role of RMs and antioxidant enzymes in oxidative stress resulting in T2DM.
Antioxidants; oxidative stress; polymorphisms; reactive metabolites; type 2 diabetes mellitus
Recent advances in the study of alcoholism have thrown light on the involvement of various neurotransmitters in the phenomenon of alcohol addiction. Various neurotransmitters have been implicated in alcohol addiction due to their imbalance in the brain, which could be either due to their excess activity or inhibition. This review paper aims to consolidate and to summarize some of the recent papers which have been published in this regard. The review paper will give an overview of the neurobiology of alcohol addiction, followed by detailed reviews of some of the recent papers published in the context of the genetics of alcohol addiction. Furthermore, the author hopes that the present text will be found useful to novices and experts alike in the field of neurotransmitters in alcoholism.
γ-amino butyric acid; alcoholism; dopamine; glutamate; serotonin
Hyperdiploid pre-B-cell acute lymhoblastic leukemia (pre-B-ALL) is a common form of childhood leukemia with very good prognosis with present day chemotherapy. However, the chromosomal composition of the hyperdiploidy has not been extensively studied and possible mechanism for this pathology remains so far conjectural.
To analyze the pattern of chromosome involvement in a cohort of childhood hyperdiploid pre-B-ALL from India and from this pattern to develop an understanding on the causation of such pathology. Whether such patients also carry translocations and FLT3 mutations in addition to their hyperdiploid karyotype.
MATERIALS AND METHODS:
One hundred and twenty-six childhood pre-B-ALL patients were studied. Bone marrow aspirate of these patients were evacuated for morphology, FAB classification, immunophenotyping and both conventional and molecular cytogenetics.
Of 126 patients with pre-B-ALL (age 2-15 years), 90 patients with abnormal karyotype showed 50 with hyperdiploid karyotype (50/90 i.e. 55.5%). Chromosomes 9, 10, 14, 17, 18, 20 and 21 were more often involved in hyperdiploidy. Chromosome 21 duplication was present in 92% of the cases. Chromosomes 5, 15, 16, 17 and Y were less often involved (18-20%) in hyperdiploidy. About 44% of patients with hyperdiploidy had additional karyotypic abnormality of which TEL-AML1 was predominant (24%). Chromosome loss was rare and accounted for 20% of the cases only. We did not find any FLT3 mutation in our patients.
In this study, the pattern of chromosome involvement in hyperdiploid karyotype of ALL patients is same as other studies except some chromosomes like 1, 6, 11, 12, 19 and 22 have some more frequent involvement than other studies. This study also showed the occurrence of TEL/AML1 fusion is more (19.8%) than other reports from India.
Abnormal mitosis; centrosome pathology; cytogenetics; hyperdiploidy; pre-B acute lymphoblastic leukemia; selective gain of chromosomes; uniparental disomy
The ABCC8 gene which encodes the sulfonylurea receptor plays a major role in insulin secretion and is a potential candidate for type 2 diabetes. The -3c → t (rs1799854) and Thr759Thr (C → T, rs1801261) single nucleotide polymorphisms (SNPs) of the ABCC8 gene have been associated with type 2 diabetes in many populations. The present study was designed to investigate the association of these two SNPs in an Asian Indian population from south India.
MATERIALS AND METHODS:
A total of 1,300 subjects, 663 normal glucose tolerant (NGT) and 637 type 2 diabetic subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES). The -3c → t and Thr759Thr were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a few variants were confirmed by direct sequencing.
The frequency of the ‘t’ allele of the -3c → t SNP was found to be 0.27 in NGT and 0.29 in type 2 diabetic subjects (P = 0.44). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetic group (P = 0.18). Neither the genotypic frequency nor the allele frequency of the Thr759Thr polymorphism was found to differ significantly between the NGT and type 2 diabetic groups.
The -3c → t and the Thr759Thr polymorphisms of the ABCC8 gene were not associated with type 2 diabetes in this study. However, an effect of these genetic variants on specific unidentified sub groups of type 2 diabetes cannot be excluded.
ABCC8 gene; south Indians; sulfonylurea receptor; type 2 diabetes
Oral cancers have been one of the leading causes of deaths particularly in the developing countries. Prime reason for this high mortality and morbidity is attributed to the delay in diagnosis and prompt treatment. Relentless research in the field of oncology has led to the advent of novel procedures for the early detection of oral cancers. Molecular biology is highly promising in this regard. It is a procedure that detects alterations at a molecular level much before they are seen under a microscope and much before clinical changes occur. Molecular studies serve as the basis by which we will eventually be able not only to augment clinical assessment and classification of oral lesions but also predict malignant potential of oral lesions, thus reducing the incidence and increasing the scope for early diagnosis and treatment of oral cancers. However, making such sophisticated tools available for the common man in developing countries is one of the most important challenges faced today.
Cytogenetics; intracellular messengers; oncogenes; oral cancer; transcriptional factors; tumor suppression gene
Familial Mediterranean fever (FMF) is autosomal recessive disease that affects people from Mediterranean region, Europe and Japan. Its gene (Mediterranean fever [MEFV]) has more than 100 mostly non-sense mutations.
The objective of the following study is to provide some phenotype-genotype correlates in FMF by categorizing the Egyptian FMF cases from Delta governorates after analysis of the four most common mutations of MEFV gene (M680I, M694I, M694V, V726A).
SUBJECTS AND METHODS:
Clinically, suspected FMF cases using Tel-Hashomer criteria were enrolled in the study. Cases were referred to Mansoura University Children's Hospital that serves most of the most middle Delta governorates, in the period from 2006 to 2011. Subjects included 282 males and 144 females, mean age of onset 9.3 ± 2.2 years. All cases were analyzed for these mutations using amplification refractory mutation system based on the polymerase chain reaction technique. Five FMF patients agreed to undergo renal biopsy to check for development of amyloidosis. Analysis of data was carried out using SPSS (SPSS, Inc., Chicago, IL, USA).
Mutation was found in 521 out of 852 studies alleles, the most frequent is M694V (35.4%) followed by M694I, V726A and M680I. 11 cases were homozygous; 7 M694V, 3 M680I and only one M694I case. Severe abdominal pain occurred in 31 (7.28%) but severe arthritis in 103 cases (24.2%). Strong association was found between arthritis and homozygous mutant compared with single and double heterozygous (72.7% vs. 33.3% and 20.24%, P < 0.001). Four amyloid cases were M694V positive.
M694V allele is the most common among Egyptian FMF especially those with amyloidosis. We recommend routine check for amyloidosis in FMF cases to statistically validate this link.
Amyloidosis; familial Mediterranean fever; Mediterranean fever gene; M694V
AIMS AND OBJECTIVES:
The present study was evaluated the atheroprotective potential of paraoxonase1 (PON1) and its Q192R polymorphism, to determine whether this polymorphism, which is responsible for differential PON1 activity plays any role in the pathogenesis, severity and extent of coronary artery disease (CAD).
MATERIALS AND METHODS:
This hospital-based cross-sectional study investigated 60 diagnosed cases of CAD and 60 age and gender matched controls. All were assessed for serum PON1 activity, PON1 Q192R polymorphism and for classical cardiovascular risk factors. Individual serum phenotyping for PON1 Q192R polymorphism was determined by double substrate hydrolysis assay. Severity of CAD was assessed by the length of intensive cardiac care unit (ICCU) stay.
Serum PON1 activity is significantly reduced in cases of CAD (92.6 ± 31.13 IU/L when compared with controls (105.26 ± 32.53 IU/L). Furthermore, serum arylesterase activity is reduced in CAD patients (90.31 ± 23.26 kU) when compared with the control subjects (101.61 ± 28.68 kU). Serum PON1 and arylesterase activities are significantly negatively correlated with the length of ICCU stay (r = −393 and r = −374 respectively). There is no significant difference in the occurrence of CAD and length of ICCU stay among the PON1 phenotypes (P = 0.92). Logistic regression analysis after adjustment of established risk factors revealed no significant association between CAD risk and PON1 Q192R polymorphism (odds ratios: 1.179 [95% confidence intervals: 0.507-2.744], P = 0.702).
SUMMARY AND CONCLUSIONS:
The current study demonstrates that the activity of the PON1 enzyme may be more important factor than the PON1 Q192R polymorphism in the severity and extent of CAD.
Coronary artery disease; paraoxonase1; paraoxonase1 Q192R polymorphism
Migraine is a chronic, neurovascular polygenic disease where genetic and environmental factors are involved in its etiology. Dysfunction of neuronal ion transportation can provide a model for predisposition for common forms of migraine. Mutations in genes encoding ion channels disturb the rhythmic function of exposed tissue that may also explain the episodic nature of migraine. Our aim was to study the single nucleotide polymorphisms of CACNA1A gene in migraine patients.
MATERIALS AND METHODS:
The subjects were the patients of migraine, in the age range of 18-80 years, diagnosed by a Neurologist, as per the diagnostic criteria of International Headache Society (IHS) Classification 2004 after excluding other causes of headache by clinical examination and relevant investigations.
The controls were the age and sex matched healthy persons from the same population excluding the relatives of patients. Only those patients and the controls, who voluntarily participated in the study, were taken and their blood samples were taken for the study. Deoxyribonucleic acid (DNA) extraction was performed according to the manufacturer's protocol for Qiagen DNA extraction kits (Qiagen, Hilden, NRW, Germany). DNA content was quantified by spectrophotometric absorption (Nanodrop Spectrophotometer, BioLab, Scoresby, VIC, Australia). Polymerase chain reaction was performed using an iCycler Thermal Cycler (Bio.Rad, Hercules, CA, USA). The polymorphic analysis of CACNA1A gene was carried out by two methods: Restriction fragment length polymorphism and sequencing.
The study included a total of 25 patients of migraine, diagnosed on out-patient department basis as per IHS Classification 2004 and compared with age and sex matched 25 healthy controls. Most of the patients 23 (92%) were below the age of 50 years. 20 of the patients (80%) were females and 5 (20%) were males. The polymorphic analysis of CACNA1A gene revealed the presence of only the wild form of the gene for the codon E993V in both case and control groups.
In our study, we could not find any polymorphism of CACNA1A gene in the selected patients. Instead the wild type of genotype was found in both patients and controls. This negative result presented here, implies that if the CACNA1A gene is involved in typical migraine (with and without aura), its contribution is very modest and therefore difficult to discern. Nevertheless, there are other genes that could be considered potential candidates for typical migraine susceptibility for which further research is needed.
CACNA1A gene; migraine; polymorphism
BCR-ABL fusion oncogene is a hallmark of Chronic Myeloid Leukemia (CML). It results due to translocation between chromosome 22 and chromosome 9 [t (9; 22)(q34; q11)]. It gives rise to translation of a 210 KDa chimeric protein (p210), leading to enhanced tyrosine kinase activity and activation of leukemogenic pathways, ultimately causing onset of CML. In case of CML, the classic fusions are b2a2 or b3a2, fusing exon 13 (b2) or exon 14 (b3) of BCR, respectively, to exon 2 (a2) of ABL. The type of BCR-ABL transcripts are thought to be have different prognosis and hence useful in clinical decision-making. The frequencies of different fusion oncogenes associated with leukemia can vary in different ethnic groups and geographical regions due to interplay of genetic variation in different ethnic populations, diverse environmental factors and living style. Moreover, earlier relevant studies from our region were carried out in small subset of patients. Therefore, objective of this study was to find out frequencies of different BCR-ABL splice variants in larger subset of CML patients.
A nested reverse transcriptase polymerase chain reaction (RT-PCR) was established to detect BCR-ABL splice variants in 130 CML patients. Sensitivity of RT-PCR and ability to detect BCR-ABL fusion gene in least possible time was studied.
BCR-ABL detection using our optimized RT-PCR protocol could be completed in 8 hours, starting from RNA extraction to Gel electrophoresis. Sensitivity of RT-PCR assay was of the order of 10−6. Out of 130 Pakistani patients, 83 (63.84%) expressed b3a2 while 47 (36.15%) expressed b2a2 transcript.
Our RT-PCR was proved to be very quick to detect BCR-ABL fusion oncogene in CML patients within one working day. Because of its sensitivity, it can be used to monitor complete molecular response in CML. BCR-ABL RT-PCR and BCR-ABL splice variants frequency in our study differs from other ethnic groups. It shows that ethnic and geographical differences exist in BCR-ABL splice variant frequency, which may have a profound effect on disease biology as well as implications in prognosis and clinical management of BCR-ABL positive leukemias.
b2a2; b3a2; breakpoint cluster region-abelson; breakpoint cluster region-abelson alternative splicing
Klinefelter syndrome (KS) is a sex chromosome disorder and has been reported to be associated with increased risk for malignancies. We report a 22-year-old male patient who was diagnosed to have chronic myeloid leukemia in chronic phase. Bone marrow cytogenetic examination revealed karyotype 47, XXY, t (9; 22)(q34, q11) suggestive of KS with presence of Philadelphia chromosome. The patient was treated with oral imatinib mesylate (400 mg/day). Complete hematological response was achieved after 2 months of therapy. The bcr-abl/abl transcript percentage measured from peripheral blood at baseline, 1 and 2 years after imatinib were 97%, 1.99%, 0.007%, respectively. He remains in complete hematological and major molecular remission after 2 years of continued imatinib therapy.
Chronic myeloid leukemia; imatinib; Klinefelter's syndrome
Raine syndrome is a rare genetic disorder with characteristic features of exophthalmos, choanal atresia or stenosis, osteosclerosis and cerebral calcifications. Most of babies with this disorder die immediately after birth. We report a baby who was 7 weeks old at the time of presentation.
Lethal; osteosclerosis; Raine syndrome
Berardinelli-Seip syndrome type 1 or Berardinelli-Seip congenital lipodystrophy 1 (BSCL1) is a very rare genetic disorder characterized by lipoatrophy, hypertriglyceridemia, hepatomegaly and acromegaloid features. Its prevalence in Egypt is not known. Here, we report case of a 12-year-old Egyptian boy with the clinical, metabolic and molecular genetics manifestations of BSCL1 including overt diabetes mellitus.
Acromegaloid features; Berardinelli-Seip syndrome type 1; diabetes mellitus; hypertriglyceridemia
Acute lymphoblastic leukemia is a malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. We describe the clinical, morphologic, immunophenotypic and cytogenetic findings in the case of a 26-year-old man with B-lymphoblastic leukemia. Surface marker analysis revealed that they are positive for CD markers CD10, CD19, CD13, CD34, CD45 and HLA-DR, but negative for CD20, CD33, CD117 and CD11C markers. Cytogenetic analysis established a novel translocation, t (9;14)(p24;q13). Apart from this, spectral karyotyping revealed an additional translocation, t (6p; 14q). This is the first documented case of B-lymphoblastic leukemia with concurrent occurrence of both abnormalities. Further studies are needed to understand the role of this abnormality in carcinogenesis.
B-acute lymphoblastic leukemia; conventional cytogenetics; Janus kinase 2; spectral karyotyping
Poland's syndrome is a rare congenital condition, characterized by the absence of the sternal or breastbone portion of the pectoralis major muscle, which may be associated with the absence of nearby musculoskeletal structures. We hereby report an 8-year-old boy with typical features of Poland syndrome, the first documented case from Uttar Pradesh, India.
Pectoralis major; Poland syndrome; symbrachydactyly; syndactyly
Rearrangements between homologous chromosomes are extremely rare and manifest mainly as monosomic or trisomic offsprings. There are remarkably few reports of balanced homologous chromosomal translocation t (22q; 22q) and only two cases of transmission of this balanced homohologous rearrangement from mother to normal daughter are reported. Robersonian translocation carriers in non-homologous chromosomes have the ability to have an unaffected child. However, it is not possible to have an unaffected child in cases with Robersonian translocations in homologous chromosomes. Carriers of homologous chromosome 22 translocations with maternal uniparental disomy do not have any impact on their phenotype. We are presenting a family with a history of multiple first trimester miscarriages and an unexpected inheritance of balanced homologous translocation of chromosome 22 with paternal uniparental disomy. There are no data available regarding the impact of paternal UPD 22 on the phenotype. We claim this to be the first report explaining that paternal UPD 22 does not impact the phenotype.
Balanced homologous chromosomal translocation; inheritance; uniparental disomy
Chromosomal heteromorphisms are described as interindividual variation of chromosomes without phenotypic consequence. Chromosomal polymorphisms detected include most regions of heterochromatin of chromosomes 1, 9, 16 and Y and the short arms of all acrocentric chromosomes. Here, we report a girl with Down-syndrome such as facies and tremendously enlarged short arm of a chromosome 22. Fluorescence in situ hybridization (FISH) with a probe specific for all acrocentric short arms revealed that the enlargement p arms of the chromosome 22 in question contained exclusively heterochromatic material derived from an acrocentric short arm. Parental studies identified a maternal origin of this heteromorphism. Cryptic trisomy 21 of the Down-syndrome critical region was excluded by a corresponding FISH-probe. Here, we report, to the best of our knowledge, largest ever seen chromosome 22 short arm, being ~×1.5 larger than the normal long arm.
Acrocentric p arms; fluorescence in situ hybridization; heteromorphism; karyotype
Split-hand/foot malformation (SHFM) is a rare condition which can be either syndromic or nonsyndromic. We report three unrelated pedigrees, one with autosomal dominant (AD) inheritance and the other two with autosomal recessive (AR) pattern. We also briefly review the published reports from India.
Autosomal dominant; autosomal recessive; ectrodactyly; Indian; split-hand/foot malformation
The role that epigenetic mechanisms play in phenomena such as cellular differentiation during embryonic development, X chromosome inactivation, and cancers is well-characterized. Epigenetic mechanisms have been implicated to be the mediators of several functions in the nervous system such as in neuronal-glial differentiation, adult neurogenesis, the modulation of neural behavior and neural plasticity, and also in higher brain functions like cognition and memory. Its particular role in explaining the importance of early life/social experiences on adult behavioral patterns has caught the attention of scientists and has spawned the exciting new field of behavioral epigenetics which may hold the key to explaining many complex behavioral paradigms. Epigenetic deregulation is known to be central in the etiology of several neuropsychiatric disorders which underscore the importance of understanding these mechanisms more thoroughly to elucidate novel and effective therapeutic approaches. In this review we present an overview of the findings which point to the essential role played by epigenetics in the vertebrate nervous system.
Behavior; cognition; development; environmental effect; epigenetics; maternal effect; neuropsychiatric disorders; plasticity; synaptic plasticity
Cytochrome P450 2D6 (CYP2D6) enzymes are involved in the metabolism of a large number of commonly prescribed drugs such as antidepressants and cardiovascular drugs. The CYP2D6 *3, *4 and *14 variants associated with the loss of enzyme function; CYP2D6 *10 and *17 variants with reduced enzyme function; and CYP2D6 *2 variant with no effect on enzyme function. Establishing the frequency of these variant alleles in Sri Lankan population would be useful for optimizing pharmacotherapy with CYP2D6-substrate drugs.
The objective of this study was to determine the prevalence of CYP2D6 *2, *3, *4, *10, *14 and *17 variants in the main ethnic groups in the Sri Lankan population.
MATERIALS AND METHODS:
A total of 90 deoxyribonucleic acid (DNA) samples (30 each from Sinhalese, Tamils and Moors) were selected from a DNA resource at the Human Genetic Unit, Faculty of Medicine, University of Colombo. This collection had been made for population genetic studies from a random population based volunteers. Genotyping was performed using published polymerase chain reaction/restriction fragment length polymorphism methods.
The prevalence of the CYP2D6 variants in Sinhalese, Sri Lankan Tamils and Moors respectively were CYP2D6 *2: 37%, 41.6% and 37.9%; CYP2D6 *3: 60.3%, 45% and 30%; CYP2D6 *4: 21.6%, 6.6% and 8.3%; CYP2D6 *10: 40%, 35% and 44%. CYP2D6 *14 and *17 variants were not identified.
CYP2D6*3, *4 and *10 variants, which are associated with reduced or loss of CYP2D6 enzyme function were found in our population in significant frequencies. CYP2D6*4, which is reported to be a Caucasian variant was also found in all three ethnic groups.
Allele frequency; cytochrome P450 2D6; Sri Lankan
This study aims at evaluating the chromosomal abnormalities and deoxyribonucleic acid (DNA) damage in cases with primary amenorrhea by karyotyping and comet assay.
A total of 30 cases of primary amenorrhea were recruited. Secondary sexual characters were assessed by Tanner staging. Chromosomal analysis was performed by conventional phytohemagglutinin stimulated lymphocyte cell culture technique. Alkaline version of comet assay was used to evaluate DNA damage.
The chromosomal pattern of 20 subjects (66.7%) was found to be normal (46,XX). Two subjects had 46,XY pattern and eight subjects had Turner syndrome (45,X or 45,X/46,XX). The comet parameters were found to be increased among subjects with 45,X monosomy, when compared to the rest of the study group and also in subjects with Tanner stage 1 when compared to stage 2.
Comet assay revealed increased DNA damage in cases with 45,X monosomy, compared with subjects with 46,XX and 46,XY karyotype, which correlated with clinical features.
Comet assay; deoxyribonucleic acid damage; karyotyping; primary amenorrhea
Leprosy (Hansen's disease) is a human chronic granulomatous infectious disease caused by Mycobacterium leprae. Several types of study support a role for host genetics in susceptibility to leprosy. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an intracellular lymphoid protein tyrosine phosphatase that has been shown to play a negative regulatory role in T-cell activation.
The aim of the present study was to find out associating the PTPN22 C1858T (R620W) polymorphism and leprosy in the Azeri population from Northwest Iran.
MATERIALS AND METHODS:
A total of 153 treated leprosy patients and 197 healthy and ethnic matched controls entered this study. We used restriction fragment length polymorphism method to type PTPN22 C1858T polymorphism.
There was no significant difference in distribution of genotype and allele frequencies of PTPN22 C1858T polymorphism between leprosy patients and controls (P = 0.641 and 0.645; respectively). Moreover, there was no significant association between different clinical findings (karnofsky performance status score, clinical forms and manifestations of leprosy) and PTPN22 C1858T polymorphism. Data showed a low frequency of the minor (T) allele by 2.3% in leprosy and 1.5% in healthy individuals.
The PTPN22 C1858T (R620W) is not relevant in susceptibility to leprosy in the Azeri population of Northwest Iran.
Gene polymorphism; leprosy; protein tyrosine phosphatase non-receptor type 22