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Home > Elucidation of Molecular Genetic Basis of Schizophrenia and Primary Microcephaly in Pakistani Population

Elucidation of Molecular Genetic Basis of Schizophrenia and Primary Microcephaly in Pakistani Population

Thesis Info

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Author

Fatima, Ambrin.

Program

PhD

Institute

Pakistan Institute of Engineering and Applied Sciences

City

Islamabad

Province

Islamabad

Country

Pakistan

Thesis Completing Year

2016

Thesis Completion Status

Completed

Subject

Natural Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/9449/1/Ambrin_Fatima_Biotechnology_2016_HSR_PIEAS_ISD_25.10.2016.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726051061

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The high degree of consanguineous marriages, languages, and religion are important factors responsible for high frequency of diverse hereditary disorders in Pakistani population. High incidence of inherited disorders is an ideal substrate to initiate molecular studies in Pakistani population. In this thesis I have systematically identified, phenotyped and sampled complex disorder (Schizophrenia) and rare Mendelian disorder (Primary Microcephaly) in families of different ethnicities/regions in Pakistan. Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. The symptoms appear in late adolescence or early adulthood, and mainly manifest as hallucination, delusions, cognitive deficit, abnormal moods and behavior. In this thesis 16 multiplex schizophrenia families were systematically identified, diagnosed and sampled from different ethnicities/regions of Pakistan, along with a second cohort of 508 unrelated Pakistani schizophrenia patients. Fifteen out of the sixteen families were excluded for the presence of pathogenic Copy Number Variations (CNVs) by genome wide array screening. While in one of the 16 families pathogenic rare novel duplication was detected on chromosome 5q14.1_q14.2 that truly segregated with the phenotype. Exome sequencing of schizophrenia families revealed three rare and eight common variants in two families. A set of top schizophrenia candidate genes (MIR137, CACNA1C, CSMD1, GRM3 and DRD2) was selected to evaluate their association with schizophrenia in Pakistani population. A case control association study revealed a significant difference in the genotype and allele frequencies of three SNPs between the patients and controls (p = 0.000). Autosomal Recessive Primary Microcephaly (MCPH) is a neurodevelopment defect, characterized by congenital reduction in Occipitofrontal Circumferance (OFC)/Head Circumference (HC) is at least 4 standard deviations (SD) below the ethnically matched, age and sex related mean. MCPH is associated with some degree of mental retardation which persists throughout their life without additional xx morphological or clinical symptoms. The prevalence of primary MCPH is 1 in 10,000 in Pakistani population. In this thesis six consanguineous MCPH families originating from different cities of Punjab were analyzed. Linkage analysis and exome sequencing revealed four novel and two known mutations in MCPH families. The findings in this study will help in understanding the disease mechanism and related pathways as well as annotating various entities of genome. This knowledge will help in efficient carrier screening, genetic counseling and prenatal diagnosis of affected families and ultimately to development of effective therapeutic approaches.
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حامد نعمانی

حامد نعمانی مرحوم
مولانا شبلی نعمانی ؒ کی ایک ہی جسمانی یادگار باقی رہ گئی تھی وہ بھی مٹ گئی، یعنی ان کے اکلوتے صاحبزادہ حامد نعمانی صاحب نے ۶۲؍ برس کی عمر میں ۲؍ ربیع الاول ۱۳۶۱؁ھ مطابق ۲۰؍ مارچ ۱۹۴۲؁ء کی شب کو جونپور میں دفعتہ وفات پائی، وہ کئی برس سے مرض قلب میں گرفتار تھے، علاجوں کے سہارے سے چلتے پھرتے تھے، مگر اندر سے کھوکھلے ہوچکے تھے، ۱۹؍ مارچ کو وہ ایک ضرورت سے جونپور گئے تھے، شام کو پہنچے، اپنا کام کیا، رات کو ۳ بجے کے قریب درد دل کا دورہ ہوا،ان کے میزبان دوست ان کے کراہنے کی آواز سن کر ان کے پاس آئے، مرحوم نے کہا کہ مجھے ذرا سہارا دے کر بٹھا دو، انہوں نے اپنے سینے کے سہارے سے بٹھا دیا، اسی کے ساتھ مرحوم نے ان کو السلام علیکم کہا، اور آخری سانس لے کر نامعلوم سفر کی منزل پر روانہ ہوگئے، انا ﷲ و انا الیہ راجعون، ۲۰ کی صبح کو لاش کار سے اعظم گڑھ آئی، اور شبلی منزل میں باپ کے پہلو میں بیٹے کو ہمیشہ کے لیے سلا دیا گیا۔
مرحوم بڑے توانا و تندرست، قوی ہیکل، بلند و بالا، اور علی گڑھ کالج کے مشہور کھلاڑیوں میں تھے، گھوڑے کی سواری اور پولو میں بھی ممتاز تھے، تحصیلداری کے عہدہ پر فائز ہوکر پنشن پائی پھر ریاست منجھولی میں منیجر ہوئے، مگر صحت کی خرابی کے سبب سے مستعفی ہوگئے، پابند صوم و صلوٰۃ، نیک دل اور بہت رحیم المزاج تھے، اپنی ذاتی زندگی میں گو وہ بہت قانع اور منتظم تھے مگر اس طرح سے جو بچتا تھا، اس کو ہمیشہ فیاضی کے ساتھ نیک کاموں میں لگادیا کرتے تھے، ۱۹۲۷؁ء میں حج بھی کیا تھا ، زکوۃ کا پورا حساب رکھتے تھے، اﷲ تعالیٰ ان پر رحمت...

Performance of Banking Industry After Privatization in Pakistan: A Case Study of Mcb Bank Limited

This research work aims to investigate the impact of privatization on the performing efficiency of MCB Bank Limited Privatization and the phenomenon of denationalization after the failure of socialism and communism globally. As the direction of enteritis was predetermined by state which in long term affected the performance of state-owned entities on many fronts even they reached at the verge of collapse and state was compelled to inject capital for their survival. Ultimately the state took drastic steps and initiated the process of denationalization and privatization to keep the industry intact in the changed scenario. In 1974, during Z.A. Bhutto regime Pakistan’s banking industry was nationalized with prime objective to address the issues of backward segments of economy but unfortunately after privatization industry was used for political motives and witnessed poor performance and financial indiscipline due to frequent interference in the affairs of banks particularly in lending activities and hiring of inefficient human resources. Resultantly banks failed to deliver as per expectation of masses and could not deliver quality customer services on one hand and accumulation of infected portfolio on the other which in turn swallowed the profitability and the capital of banks. It is revealed that bank has tremendously performed in all Key Performing Indicators, it has improved its profitability manifold, deposit base is significantly enhanced and became more liquid and solvent.

Determination of Efficacy of Bioactive Compounds of Eucalyptus Spp. Extracts Against Spot Blotch of Wheat

Spot blotch disease caused by Bipolaris sorokiniana Sacc. is a severe constraint with 30-70% estimated yield losses to wheat production in warmer regions of the world. The purpose of this study was to evaluate crude extracts of Eucalyptus camaldulensis Dehn and Eucalyptus torelliana F. Muell (Myrtaceae) for their fingicidal activity against Bipolaris sorokiniana and if they can be used as a spot blotch disease management strategy. In was observed that flowering buds are most potential part of both plant species compared to leaves and bark. The ethanol, methanol and aqueous crude extracts of E. camaldulensis flowering buds inhibited mycelial growth up to 97, 91 and 67% While; the E. torelliana extracts restricted mycelial growth of 75, 74, and 47% respectively. The E. camaldulensis flowering buds ethanol extract provided maximum inhibition zone of 29.10±0.92 with 10mg/well and minimum inhibitory concentration value of 25mg/ml. The minimum mean length of conidiophores observed (78μ) and mean width (3.63μ) for treatment of E. camaldulensis flowering buds ethanol extract at 10% concentration over control 141μ length and 7.33μ width. A range of variations in mean length of B. sorokiniana conidia observed from 49-74µ and mean width from 19-25µm having 1-7 septa and light brown colour. In control treatments mean length range from 75-77µ and width from 25-28µ. The extract treated hyphae were damaged, collapsed and thinner as compared to control treatment. In 10µl spore suspension the highest number of conidia (34±9.63) found in essential oil treatment at 0.5% concentration followed by at 1% concentration (30.±8.17) compared to distilled water treatment (53±10.34). The E. torelliana flowering buds methanol extract at 10% concentration provided the smallest fresh weight (0.026g) and dry weight (0.02g) of fungal biomass. The In-vivo effects of E. camaldulensis and E. torelliana flowering buds extracts against aggrasive isolate of spot blotch were observed on susceptible variety bhakkar 2001 of wheat. The pesticidal effect of flowering buds extracts with different spray schedules as well as different concentration was highly significant (P<0.05) for both of grain yield/spike and 1000 grain weight. The E. camaldulensis flowering bud extractsin ethanol produces highest number of grains/spike (50, 48 & 43) as compared to E. torilliana 41, 38 & 33 grains/spike underspray I, Spray II and Spray III schedule respectively at 10% concentation. In case of number of grains per spike, for each unit increase in disease severity, 0.395 units decrease observed in number of grains/spike.The R2 0.473 indicates that 47.3% variations in grains yield/spike are caused by disease severity. There is 0.269 unit’s decrease in 1000-grains weight (g) with 51.03 unit’s increase of disease severity. The relationship of disease severity was negatively correlated with yield contributing parameters. The R2 (0.574) means that 57.4% variation in 1000 grains weight is explained by predictor variable. Standard error value (3.171) represents the typical deviation between the actual 1000 grain weight and what the model predicted to be. In simple there are 3.171g typical fluctuations around the regression line E. camaldulensis flowering buds extracts were further investigated for the most active compounds. Partitioning of crude ethanol extract was done with hexanes, Toluene, Dichloromethane, ethyl acetate, n-butanol and water. Hexanes part was most active in mycelial growth assay with the maximum 86% inhibition. Two compounds, A and B were purified from hexane part through flash Column Chromatography (FCC) by silica gel, Prep-TLC and Prep-HPLC. The recovered compounds showed high antifungal activity against B. sorokiniana (spot blotch). The chemical analysis of active compounds by HPLC, MS, FT-IR and NMR revealed the presence of hydrocarbons. These compounds are >C=O carbonyl functional group containing terpenoids that form crystalline products. The results indicate that E. camaldulensis flowering buds extracts contain antifungal compounds and can be exploited as a spot blotch disease and other fungal pathogens management strategy if formulation is developed in future.