فقہی اختلافات کے مابین امام شعرانی اور شاہ ولی اللہ کے اسالیب تطبیق

In the Islamic Sharia there are two types of texts, as for the first one, there is no need for any interpretations. For instance: Tauhid (unity of Allah), while few interpretations have modiefied with the changing circumstances. The expertises of Islamic jurists highlight the interpretations of the text according to prevailing social and political environment which can create harmony between Islamic Sharia and importunity of nature. Imam Sharani and Shah Wali Ullah are those personalities who evaluated the intellectual efforts of Islamic jurists and describe their diligencial and margenial secondary level differences. They created a road of conformity between their minor level marginal differences which are legitimate. Imam Sharani and Shah Wali Ullah‘s methodologies of uniformity represent the facts that differences in the approaches of jurists, which are considered as segregation in the reality that is benevolence for Muslim Ummah. Their methodologies of uniformity are not only practical but also very useful in the context of global village. In this age ethical, social, and family problems can be solved through the method of uniformity. For the solution of issues like intellectual extremism, prejudice and terrorism, Imam Sharani and Shah Wali Ullah‘s methodologies of uniformity are beaconhouse.

Genetic Mapping and Mutation Analysis of Genes Causing Autosomal Recessive Hypotrichosis and Ectodermal Dysplasias

In the present research study twenty families segregating autosomal recessive form of hypotrichosis and ectodermal dysplasias, and one X-linked hypohidrotic ectodermal dysplasia have been characterized at clinical and molecular levels. Ten families presented clinical features of various types of isolated hair loss disorders, six isolated nail dysplasias and five ectodermal dysplasias. Genotyping using microsatellite markers established linkage in seventeen families to previously known genes. Subsequently, Sanger cycle sequencing revealed three novel missense/nonsense variants in FZD6, PVRL4 and ELOVL4 genes, and eight previously reported mutations in HR, DSG4, LIPH, LPAR6, RSPO4, EDA, and PVRL4 genes. In two families, SNP-based human genome scan mapped novel homozygous regions on two different chromosomes. Further, exome sequencing identified the first disease causing mutation in a keratin gene. In a family, collected from a remote region of Pakistan, all four affected members manifested coarse, lusterless, dry, and tightly curled woolly hair with sparse eyebrows and eyelashes. Whole Genome Scan (WGS) identified 15 cM genetic interval on chromosome 17q21.2-17q22. Whole exome sequencing identified the first disease causing mutation (p.Leu317Pro) in KRT25 gene. Linkage in eight other families, with hair loss disorders, was established to the genes HR on chromosome 8p21.3, LIPH on 3q26.33-q27.3, DSG4 on 18q21.1 and LPAR6 on 13q14.11-q23.21. DNA sequence analysis identified previously reported mutations including two missense (p.Pro1157Arg, p.Cys690*) in HR, a two base-pair deletion (c.659_660delTA) in LIPH, a large deletion (Ex5_8del) in DSG4 and a missense (p.Asp63Val) in LPAR6. In silico analysis of mutated and normal modelled LPAR6 proteins revealed abnormal phospholipid signaling pathway leading to hypotrichosis. One of the families failed to show linkage to the known genes. The second group of six consanguineous families, segregating five different types of nail abnormalities, was characterized at clinical and molecular levels as well. Two of these families failed to show linkage to the previously reported genes. Human genome scan was performed in one family, which led to the identification of a novel locus on chromosome 4p15.0-4p15.2. DNA sequence analysis in three families identified a Abstract Genetic Mapping and Mutation Analysis of Genes Causing Autosomal Recessive Hypotrichosis and Ectodermal Dysplasias XXVIII novel homozygous missense mutation (p.Gly422Asp) in FZD6 and a recurrent 26 bp deletion mutation (-9- +17del26) in RSPO4 gene. Screening HPGD gene in two families, mapped to Isolated Congenital Nail Clubbing (ICNC) locus on chromosome 4q34.1, failed to detect any potential disease causing sequence variant. In five families, three different forms of ectodermal dysplasias were identified. In two of these families, segregating ectodermal dysplasia syndactyly syndrome (EDSS), screening PVRL4 gene revealed two mutations including a novel nonsense (p.Asp61*) and a previously reported missense (p.Pro212Arg). Another family showed segregation of a rare form of neuro-ichthyotic syndrome in autosomal recessive manner. DNA sequence analysis identified a novel homozygous nonsense mutation (p.Tyr26*) in ELOVL4 gene. In a family with hypohidrotic ectodermal dysplasia (HED), sequence analysis detected a recurrent missense mutation (p.Arg155Cys) in the X-linked EDA gene. The second family segregating autosomal recessive form of HED, screening EDAR gene failed to identify potential disease causing sequence variants. The research work presented in the thesis contributed in publication of the following articles. 1. Raza SI, Dar R, Shah AA, Ahmad W (2014). A homozygous nonsense mutation in the PVRL4 gene and expansion of clinical spectrum of EDSS1. Annals of Human Genetics (In Press). 2. Raza SI, Muhammad D, Jan A, Ali RH, Hassan M, Ahmad W, Rashid S (2014). In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis. PLOS One 9: e104756. 3. Mir H, Raza SI, Touseef M, Memon MM, Khan MN, Jaffar S, Ahmad W (2014). A novel recessive mutation in the gene ELOVL4 causes a neuroichthyotic disorder with variable expressivity. BMC Med Genet 15: 25 4. Raza SI, Muhammad N, Khan S, Ahmad W (2013). A novel missense mutation in the gene FZD6 underlies autosomal recessive nail dysplasia. British Journal of Dermatology 168: 422-425. Abstract Genetic Mapping and Mutation Analysis of Genes Causing Autosomal Recessive Hypotrichosis and Ectodermal Dysplasias XXIX 5. Mehmood S, Raza SI, Younas M, Farhad I , Shahi S, Ayub M, Khan S, Jan A, Ahmad W (2014). Homozygous disease causing mutations in the human hairless gene (Submitted to Iranian Journal of Medical Genetics). 6. Raza SI, Ansar M, Regie LP, Ahmad W, Leal SM (2014). Exome Sequencing identified a disease causing variant in the type I keratin gene KRT25 (In preparation)