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Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders

Thesis Info

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Author

Ullah, Irfan

Supervisor

Wasim Ahmad

Program

PhD

Institute

Quaid-I-Azam University

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2017

Thesis Completion Status

Completed

Subject

Natural Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/7862/1/Irfanullah%20PhD%20Thesis.%20Genetic%20Mapping%20and%20Mutation%20Analysis%20of%20Genes%20Causing%20Human%20Hereditary%20Skeletal%20Disorders.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726303039

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Genetic defects in the complex processes of embryonic development of the skeleton and its postnatal maintenance result in different types of clinically diverse and genetically heterogeneous skeletal disorders. This presents a diagnostic challenge because of their nonspecific presentation, variable clinical features, highly overlapping phenotypes and lack of recognition as a discrete clinical entity. The research work, presented in this dissertation, describes clinical and molecular investigations of fourteen families (A-N) segregating various forms of skeletal disorders in autosomal recessive pattern. Clinical examinations were performed at local Government hospitals. Blood samples were collected from both affected and unaffected members of the families. Genomic DNA, extracted from the blood samples, was used for microsatellite and SNP based genetic mapping and whole exome and chain termination sequencing. Clinical features, observed in affected members of six families (A-F), were analogous to a condition named as mucopolysaccharidosis. Linkage in these families was established to chromosome 16q24.3 harboring GALNS gene. Sanger sequencing revealed two novels (p.Phe216Ser, p.Glu121Argfs*37) and two previously reported mutations (p.Pro420Arg, p.Arg386Cys) in GALNS gene in the six families. In silico analysis predicted that the missense mutations affect structure and function of the GALNS protein. Clinical and radiographic examinations of affected members in three families (G-I) underscored the manifestations of acromesomelic dysplasia. Microsatellite based genotyping followed by sequence analysis of the NPR2 gene identified three novel missense mutations (p.Arg749Trp, p.Arg601Ser, p.Leu314Arg) in the families. Human genome scan using SNP microarray followed by exome sequencing discovered a potentially casual frameshift mutation (c.594-595insT; p.Gln198Thrfs*21) in a novel gene KIAA0825 in the family J segregating post-axial polydactyly in an autosomal recessive manner. Affected individuals in family K exhibited peculiar clinical features including post axial polydactyly, speech impairment, hearing impairment of variable degree and proportionate short stature. This condition represented mild form of Joubert Abstract Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders XVIII syndrome. Whole exome sequencing in the family revealed a novel in-frame deletion mutation (c.1115-1117delCCT; p.Ser372del) in the MKS1 gene. In silico analysis revealed that Ser372 residue resides in the “B9” interacting region of the MKS1 protein and inframe mutation (p.Ser372del) causes alteration in the conformation of mutant protein with two extra α helixes. The present study described three families (L-N) with split hand/foot malformations. In two families (L, M), genetic mapping followed by Sanger sequencing detected a novel frameshift mutation (c.300-306dupAGGGCGG; p.Leu103Argfs*52) in the WNT10B gene. In the third family (N), whole exome sequencing accompanied by SNP microarray, identified six nucleotides duplication (c.217-222dupCACCCG; p.His73_Pro74dup) in a novel causative gene HOXD8. The work presented in the dissertation resulted in the following publications. 1. Irfanullah, Saadullah Khan, Imran Ullah, C. Arnoud Meijer, Marlies Laurense Bik, Johan T den Dunnen, Claudia AL Ruivenkamp, Marriët JTV Hoffer, Gijs WE Santen, Wasim Ahmad (2016). Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: expanding the phenotypic spectrum of MKS1-related ciliopathies. American Journal of Medical Genetics Part A 9999A:1–5 2. Irfanullah, Muhammad Umair, Saadullah Khan, Wasim Ahmad (2015). Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families. Annals of Human Genetics 79: 238–244 3. Abdul Aziz, Irfanullah, Saadullah khan, Faridullah khan zimri, Noor Muhammad, Sajid Rashid, Wasim Ahmad (2014). Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families. Gene 534: 265–271. 4. Irfanullah, Abdul Nasir, Sarmad Mahmood, Sohail Ahmed, Muhammad Ikram Ullah, Asmat Ullah, Abdul Aziz, Syed Irfan Raza, Khadim Shah, Saadullah Khan, Muhammad Jawad Hassan, Wasim Ahmad (2016). Identification and in silico analysis of GALNS mutations causing Morquio A syndrome in eight consanguineous families. Turkish Journal of Biology: DOI:10.3906/biy-1607-81 Abstract Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders XIX 5. Asmat Ullah, Ajab Gul, Muhammad Umair, Irfanullah, Abdul Wali, Farooq Ahmad, Abdul Aziz, Wasim Ahmad (2017). Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation. Genetics and Molecular Biology (Submitted) 6. Irfanullah, Muhammad Ansar, Saadullah Khan, Abdul Aziz, Wasim Ahmad. Exome sequencing revealed a novel gene KIAA0825 underlying autosomal recessive postaxial polydactyly (In Preparation). 7. Irfanullah, Saadullah Khan, Maaike Verschuren, Marlies Laurense Bik, Johan T den Dunnen, Claudia AL Ruivenkamp, Marriët JTV Hoffer, Gijs WE Santen, Wasim Ahmad. Human HOXD8 is a novel candidate gene causing autosomal recessive split hand foot malformation in a large Pakistani consanguineous family (In Preparation) 8. Irfanullah, Syed Zohaib Tayyed Gilani, Saadullah Khan, Wasim Ahmad. Homozygous mutations in NPR2 gene underlying Acromesomelic dysplasia in Pakistani families (In preparation)
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شاہ عزالدین پھلواروی ندوی

شاہ عزالدین پھلواروی ندوی
شاہ عزالدین پھلواروی علمی اور دینی حلقوں کے لئے محتاج تعارف نہیں، اپنے مواعظ اور تصانیف کی وجہ سے خاصے معروف ہیں، ابھی چند ہی مہینہ کی تو بات ہے جب انھیں عربی زبان اور اسلامی علوم میں مہارت کی بناء پر حکومت ہند نے اعزاز عطا کیا تھا، اور معارف نے اس سلسلہ میں انھیں مبارکباد دی تھی، کسے معلوم تھا کہ وہ اتنی جلد اس دنیا سے رخصت ہوجائیں گے۔
ادھر کچھ عرصہ سے ان کی صحت مضمحل رہنے لگی تھی، اس لئے انھوں نے سفر ترک کردیئے تھے، لیکن پورنیہ کے کچھ لوگ ان کے بے حد معتقد تھے، ان کی آرزو تھی کہ وہ اپنی تشریف آوری سے انھیں عزت بخشیں اور انھیں اپنے مواعظ سے مستفید فرمائیں، شاہ صاحب نے ناسازی مزاج کا عذر کیا، مگر جب معتقدین کا اصرار جاری رہا تو آمادہ ہوگئے تاکہ ان کے دلوں کو ٹھیس نہ پہنچے، مومن کے دل کو خوش کرنا بڑے ثواب کا باعث ہے، انھیں اس سلسلہ میں آقائے دو جہاںﷺ کی ہدایات یاد تھیں، اس لئے اپنی تکلیف کو نظرانداز کرکے آمادہ سفر ہوگئے، راستہ بخیر گزرا، پورنیہ پہونچ کر بھی ایک آدھ دن طبیعت ٹھیک رہی لیکن پھر ضعف کے ساتھ درد سینہ کی شکایت محسوس ہوتی، جو برابر بڑھتی رہی، جب مقامی دوا دارو سے طبیعت قابو میں نہ آئی، تو لوگ کسی بڑے ڈاکٹر کو بلانے کے لئے شہر گئے، مگر ساری تگ و دو بے کار ثابت ہوئی اور بالآخر وطن سے دور عزیزوں سے مہجوری کے عالم میں جان جان آفریں کے سپرد کردی، نعش پھلواری لائی گئی اور خاندانی قبرستان میں سپردخاک کئے گئے، وہ مجھ سے عمر میں چند سال بڑے تھے، تعلیم میں بھی دو تین درجے آگے تھے، لیکن طلبائے ندوہ کی انجمن الاصلاح میں میرا ان...

فکر اقبال کے تناظر میں تہذیبی تصادم

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Boundary Layer Flows and Heat Transfer of Cross Fluid

The study of generalized Newtonian fluid (GNF) is a topic of practical interest in fluid mechanics. The GNF is non-Newtonian in nature, although its constitutive equation is generalized form of Newtonian fluid. Researchers are devoting their studies to explore different subclasses of GNF. Despite of the abundant research work in this field, an important subclass of GNF namely the Cross fluid has not been given due attention. The objective of this research work is to concentrate on the flow and heat transfer characteristics of Cross fluid. The inaugural work has been presented in this thesis by bestowing the boundary layer equations of Cross fluid in different coordinate systems. This has opened new doors for researchers to carry out further research in this direction. In this thesis, a theoretical study is done to explore the flow and heat transfer characteristics of Cross fluid. The reported work presents the modelling of the boundary layer equations of GNF using the Cross viscosity model and further bestows the numerical solution regarding these equations. The current research work covers the flow of Cross fluid past a planer as well as radially stretching sheet and stretching cylinder. Moreover, investigations are done on the mixed convection flow, Falkner-skan flow, nano boundary layer flow and stagnation point flow of Cross fluid. Several effects are taken into consideration including the impact of activation energy, melting phenomenon, linear and non-linear radiation, heat generation/absorption, multiple slip effects, variable thermal conductivity, Newtonian heat and mass conditions. The modelled problems are numerically handled by two numerical techniques namely the shooting method and bvp4c in MATLAB. The results presented in this thesis are verified by making comparison with already available results in literature for reduced cases and excellent compatibility is achieved. From the obtained results, it is observed from that the progressive value of the local Weissenberg number reduces the velocity distribution while the temperature of the fluid rises. However, quite an opposite trend is exhibited by velocity and temperature profiles for growing values of the power-law index.