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Characterization of a New Locus for Autosomal Recessive Intellectual Disability Arid in Pakistani Population

Thesis Info

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Author

Rasheed, Faiza

Program

PhD

Institute

University of the Punjab

City

Lahore

Province

Punjab

Country

Pakistan

Thesis Completing Year

2018

Thesis Completion Status

Completed

Subject

Molecular Biology

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/10789/1/Faiza_Rasheed_Molecualr_Biology_2018_UoP_Punjab_PRR.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725678287

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Intellectual disability is a neurodevelopmental disorder with 1-3 % prevalence in the world population and characterized by limitations in intellectual functioning and adaptive skills with intelligence quotient (IQ) below 70 and inception before 18 years age of an individual. Molecular basis of intellectual disability in Pakistani population is not well studied and present study was designed to fill the gaps in the current knowledge of causative genes/loci responsible for intellectual disability in Pakistani population. This study is part of an institutional project on intellectual disability being executed in “Genetic Diseases lab” of the Centre of Excellence in Molecular Biology (CEMB). Forty five families with two or more affected individuals segregating intellectual disability were ascertained from Punjab province. For confirmation of genetically transmitted intellectual disability and exclusion of environmental causes, complete medical history of affected individuals and their family was documented and written informed consents were obtained. Twenty six consanguineous families, predominantly first cousin marriages, were selected for further study and screened for exclusion of twelve already reported intellectual disability loci. Three families, designated as PKMR173, PKMR 228 and PKMR 116 were found to be linked with MRT11, MRT10/20 and MRT23 respectively. Next generation sequencing/high throughput sequencing was carried out on chromosomal DNA of the affected and one unaffected member in the remaining i.e. unlinked families. Novel mutations in genes already associated with intellectual disability or related disorders were found in four families. A missense mutation in gene WDR73 segregated with phenotype in PKMR242 resulting in amino acid change of (p.(Phe325Ser)) and a missense mutation in protein FRY segregated with phenotype in PKMR264 with amino acid change of (p.(Val761Ile)). A nonsense mutation in GPT2 segregated in PKMR 281 with an amino acid change of (p.(Arg404*)) and a missense mutation in FLNA segregated in PKMR 321 with an amino acid change of (p.Thr1685Met)). Genome wide scan on DNA in family PKMR 177 resulted in mapping of a 34.5 Mb long novel locus along with frameshift mutation in a novel gene SYNRG on chromosome 17p11.2-q22 with maximum two point LOD score (Zmax) of 2.8 at recombination fraction θ=0. This novel region was also found in four other families PKMR15, PKMR 65, PKMR 72 and PKMR 274, however, causative gene was different in additionally linked families. Another 23.95 Mb long novel region was mapped in PKMR 225 on chromosome 6p23-p21.2 with moderate to severe level of intellectual disability. Two potential novel regions of 1.36 Mb and 32.58 Mb length, were mapped in PKMR 165 loop-1 and loop-2 on chromosome 9q31.3-q33.2 and chromosome 3p24.1-p14.2 respectively. In PKMR 199 three potential candidate regions were mapped on chromosome 6q24.1-q24.3, 8q24.13 q24.21 and 20p12.3 of 0.47 Mb, 0.16 Mb and 12.9 Mb respectively. In conclusion, this study is a significant contribution in identification of causes of intellectual disability in Pakistani population and will help to devise strategies to combat with this disorder in a well-organized way. This study is also expected to enlarge the current repository of genes/loci in Pakistani population.
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تقریظ سوئم

تقریظ سوئم
بسم اللہ الرحمن الرحیم
نحمدہ ونصلی علی رسولہِ الکریم

مُوصوف ایک علمی گھرانے سے تعلق رکھتے ہیں۔ دینی علوم کے حوالے سے ان کے بزرگوں کی خدمات اظہر من الشمس ہیں ۔اِن کی کتاب ــ ’’ نگارشاتِ راشد‘‘ ایک علمی خزانہ ہے اِس میں طلباء و طالبات کے لیے متعدد مضامین شامل کی گئی ہیں۔ جو اپنی نظیرآپ ہیں حافظ محمد اکرم راشدؔ نے دیگر کتب اور مضامین سے خوشہ چینی کی بجائے فی البدیہہ مواد پیش کرنے کی مساعی جمیلہ کی ہے ۔ اِ ن کی تحریر میں چاشنی اور ندرت ہے۔ اِن کے مضامین جو’’ نگارشاتِ راشد ‘‘کے نام سے زیورِ طباعت سے مرصعّ ومزیّن ہو رہے ہیں عام قاری کے لیے بالعموم اور طلباء و طالبات کے لیے بالخصوص ممدو معاون ثابت ہوں گے۔ ادارہ کے مقابلہ جات ہوں یا ضلعی اور ڈویژن لیول کے مقابلہ جات ’’ نگارشاتِ راشد‘‘ میں شامل شدہ مضامین کفایت کریں گے ۔ یہ طلباء کے لیے نعمت مترقبہ سے کم نہ ہے ۔ موصوف کا ادبی دنیا میں ایک نام ہے اِ ن کو دیکھ کر متقدمین ادباء کی یاد تازہ ہو جاتی ہے ۔ دورانِ ملازمت بھی ادبی پروگرام کے حوالے سے محکمہ تعلیم میں اِن کی تحریریں محو گردش رہی ہیں ۔ اور انعام و اکرام کی حقدار گردانی گئی ہیں۔
اللہ تعالیٰ اِن کو مزید ایسے شاہ پارے پیش کرنے کی توفیق عطا فرمائے ۔
رانا محمد اظہر خاں
چیف ایگزیکٹو آفیسر (ایجوکیشن)
ڈسٹرکٹ ایجوکیشن اتھار ٹی ، رحیم یار خاں

الشفاء بتعریف حقوقِ مصطفیٰ ﷺ کا تعارفی و تجزیاتی مطالعہ An Analytical Study of the “Al-Shifā Ba Ta‘rīf-e-Ḥuqūq-e-Muṣṭafā”

The most prominent and living name among the African biographers is Qazi Ayaz Mālkī. His book “Al-Shifā Ba Ta‘rīf-e-Ḥuqūq-e-Muṣṭafā” has an important place in the books of Sīrah and also has the status of the most popular book among all kinds of people. This book is also called Kitab-e-Shifā (meaning the one who revives hearts and heals from heart diseases). The reason for writing this book was that the people were becoming oblivious to the obligatory status and virtues of the Holy Prophet ﷺ and were becoming completely incapable of paying their dues. In these circumstances, the demand for preparation and compilation of a collection of rights and manāqibs related to it became intense and he compiled this magnificent book. On the one hand, it teaches love and respect for the Prophet (peace and blessings of Allah be upon him) and on the other hand, it mentions his rights and rewards for fulfilling them. The writing style of the book is simple and smooth as well as eloquent. The book is not so long that it would be too long for the reader to comprehend, nor is it so short that it would not be possible to get access to the concepts and demands due to its brevity. The people have made this book their favorite and have been studying it and the biographers have adopted Al-Shifā as an authoritative and reliable source. Because of its importance and usefulness, an introductory and analytical study of this book will be presented in this article.

Ecobiological and Allelochemical Characterization of Selected Invasive Plants of Pothwar Region of Pakistan

Pothwar region, Pakistan is a hot spot for biodiversity, but the vegetation is constantly under pressure of exotic invasive plants. Phytosociological studies help to understand extent of biological invasion. Multiple analyses of ecological parameters at different locations derive general explanations of impact on species diversity in plant communities. The current study assessed impact of selected invaders viz. Parthenium hysterophorus L., Lantana camara L., Xanthium strumarium L. and Broussonetia papyrifera (L.) L’Herit. ex Vent. invasion on native flora in Pothwar region of Pakistan. Paired plot experimental design with two categorical factors; invaded and non-invaded (control) under same habitat conditions was used for sampling. Differences in number of species (S), abundance (N), species richness (R), evenness (Jꞌ), Shannon index of diversity (Hꞌ) and Simpson index of dominance (λ) were calculated using PRIMER-7 software package. Ecological indices were compared between invaded and control plots by t-test series using IBM SPSS v. 21 software. Control plots harbored by an average of 0.9, 1.74, 1.28 and 1.3 more individuals per 10m2 respectively. The control category was diverse (Hꞌ=1.73, 2.56, 2.15, 2.00) than invaded category (Hꞌ=1.53, 1.56, 1.65, 1.82) for four studied invaders. Similarly, control plots showed higher value of Jꞌ and λ for all the studied sites. The higher value of species richness in control plots shows heterogeneous nature of communities and vice versa in invaded plots. The lower value of index of dominance in invaded plots shows less sample diversity than control ones. This decrease in number of species directly affects α- diversity in invaded plots. At multivariate scale, ordination (nMDS) and ANOSIM showed significant magnitude of differences between invaded and control plots in xvii all sites. The decrease in diversity indices in invaded over control sites indicated that plant communities become less productive due to invasion; hence a threat to plant diversity. Invasion impact was observed as Lantana camara > Xanthium strumarium > Parthenium hysterophorus > Broussonetia papyrifera. Results suggested appropriate control measures for studied invaders. Radish seed germination bioassay with methanol extracts harboring 0.05 gmL-1 of root, leaves, flowers and stem of selected invaders indicated L. camara leaves and X. strumarium fruits as most phytotoxic plant parts. Fractionation and bioassay guided isolation of allelochmicals from L. camara leaves against monocot (Phalaris minor Retz. & Avena fatua L.) and dicot (Rumex dentatus L. & Chenopodium album L.) weed test species provided evidence about herbicidal potential of test plant species. Among ethyl acetate, hexane, chloroform and aqueous methanolic extract fractions, ethyl acetate fraction was shown to be most inhibitory to selected weed test species. Through flash column chromatography using mobile phase of Hexane : Ethyl acetate (60:40), 31 fractions were collected in small vials and tested for inhibition activity against radish seeds. Fraction with highest inhibition activity was subjected to GC-MS analysis that shows compound as ‘Vitexin’. To the best of our knowledge Lantana camara leaves have not been previously reported to possess flavonoid compound ‘vitexin’ and tested against weeds of wheat crop. So this investigation has provided a clue about its herbicidal importance for further research.