مشکل الحدیث کے حل میں ملا علی قاری ؒ کا منہج۔ایک تجزیاتی مطالعہ

The Problematic narration has always been under the special focus of the commentators of Hadith. This important branch of Hadith sciences, in fact, removes all objections that arise on the text of an authentic narration of the Holy Prophet (S.A.W). Mulla Ali Al-qari, being a famous commentator has opted for a comprehensive pattern in solving such problematic narrations in his famous commentar0y on Mishqat Al-masabih named Mirqat Al-mafatih. This article is an effort to explore his style by presenting ten examples from this voluminous commentary. Qari has at first, investigated the authenticity of such narration. He has tried to present the views and interpretations of his predecessor scholars such as Nawavi, Ibne-Hajar, Khattabi, etc. He seems to owe a clear viewpoint about this kind of narration that prophetic sayings after being confirmed and authentic as per principles set in Hadith Sciences, must be interpreted in a way that testifies the sanctity of that narration. This research concludes that problematic narrations have been interpreted by Muslim scholars of every age according to the knowledge they possessed. In this modern age of Science and technology, if any such narration has multi interpretations only one may be preferred which is supported by the available modern research It will surely make non-believers inclined to Islam and its eternal teachings.

Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages

To function and respond effectively to the dynamic external environment, skin, the most exposed part of the human body and its appendages possess a significant ability to regenerate in a sensibly controlled fashion. When this finely tuned homeostatic system is disrupted, skin diseases such as genodermatoses may arise, which represents a complex group of acquired and congenital ectodermal disorders, personifying an investigative challenge due to highly variable and overlapping clinical phenotypes, non-specific representation, genetic heterogeneity and lack of recognition as a discrete clinical entity. In the present research, eighteen consanguineous families (A-R) segregating diverse forms of hereditary ectodermal disorders were investigated at clinical and molecular level. Subsequently extracted DNA from given blood was processed for genetic trialing using microsatellite markers, SNP microarray, whole exome and Sanger’s sequencing. The study led to the identification of two novel genes, first report of involvement of U2HR in causing complete hairloss, and few novels and previously reported mutations in genes causing skin disorders. Clinical topographies, witnessed in affected members of seven families (A-G), were analogous to isolated hereditary hypotrichosis. Linkage in two of these families was established to chromosome 3q26.33-q27.3 residing LIPH gene. Subsequently sequencing revealed two novel mutations (p.Arg110*, p.Pro311Leufs*3) in the LIPH gene. In another family, a novel compound heterozygous variant (p.Ser1589Tyr/p.Ala1092Glu) was identified in a potentially novel gene EXPH5. Search for linkage and disease causing variants in rest of the four families was not successful. Linkage in three families (H, I, J), segregating atrichia with papular lesion (APL), was established to hairless gene HR on chromosome 8q21.3. Sequence analysis of the HR gene revealed a novel non-sense variant (p.Trp847*) in family H. In two other families genetic sequence exploration identified a novel homozygous missense variant (p.Arg20Leu) in one of the upstream regulatory regions, U2HR, of the HR gene. In silico analysis of mutated and normal modelled U2HR proteins exposed abnormal regulation of HR translation leading to APL. Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages xi Three consanguineous families (K, L, M), presenting different types of nail dysplasias, were investigated in the present study. Haplotype analysis followed by sequence analysis identified a novel variant (p.Gln89*) in the HOXC13 and prior stated (p.Ala88Val) in the GJB6 gene. In the third family, segregating Koilonychia, whole exome sequencing failed to detect disease causing variant. A combination of SNP genotyping, exome and Sanger sequencing was used to genetically characterize ichthyosis and Kindler syndrome in five families. In family N, segregating X-linked ichthyosis, a deleted region (1.67 Mb) including STS gene on chromosome Xp22.3 was found a responsible factor. Genetic mapping followed by exome and Sanger sequencing identified a novel (p.F9Lfs*23) and a recurrent splice site variant (c.1718+2A>G) in the FERMT1 gene on chromosome 20p13 in two families segregating Kindler Syndrome. In family Q with ichthyosis, a single potential homozygous region (212-216 Mb) was mapped through SNP microarray on chromosome 2 in all the affected individuals. Further analysis lead to the identification of a rare splice site variant (c.938-7T>C) in potentially novel gene XRCC5. In the fifth family with ichthyosis and hair loss, a disease causing variant (p.Asp63Val) was detected in the LPAR6 gene. An extensive study on diverse cases of genodermatoses has been performed, which provided a comprehensive understanding about related diseases, their molecular pathways and probability of identifying novel molecular players responsible for causing several dermatological diseases. This provided an insight information for formulating the missing links between previously known pathological reasons/ pathways. This will support to design procedures for gene therapies for disorders involving human skin. The research work, presented here, contributed to the publications of following articles in internal peer-reviewed journals. 1. Mehmood S, Raza SI, Van Bokhoven H, Ahmad W (2017). Autosomal recessive transmission of a rare HOXC13 variant causes pure hair and nail ectodermal dysplasia. Clinical and Experimental Dermatology doi: 10.1111/ced.13115. 2. Mehmood S, Jan A, Raza SI, Ahmad F, Younus M, Irfanullah, Shahi S, Ayub M, Khan S, Ahmad W (2016). Disease causing homozygous variants in the human hairless gene. International Journal of Dermatology 55: 977-81 Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages xii 3. Mehmood S, Shah SH, Jan A, Younus M, Ahmad F, Ayub M, Ahmad W (2016). Frameshift sequence variants in the human Lipase-H gene causing hypotrichosis. Pediatric Dermatology 33: e40-2 4. Ali RH, Mahmood S, Raza SI, Aziz A, Irfanullah, Naqvi SK, Wasif N, Ansar M, Ahmad W, Shah SH, Khan BT, Zaman Q, Gul A, Wali A, Ali G, Khan S, Khisroon M, Basit S (2015). Genetic analysis of Xp22.3 micro-deletions in seventeen families segregating isolated form of X-linked ichthyosis. Journal of Dermatological Science 80: 214-7 5. Mehmood S, Jan A, Muhammad D, Ahmad F, Mir H, Younus M, Ali G, Ayub M, Ansar M, Ahmad W (2015). Mutations in the lipase-H gene causing autosomal recessive hypotrichosis and woolly hair. Australasian Journal of Dermatology 56: e66-70 6. Shah K, Mehmood S, Jan A, Abbe I, Ali RH, Khan A, Chishti MS, Lee K, Ahmad F, Ansar M, University of Washington Center for Mendelian Genomics, Shahzad S, Nickerson DB, Bamshad MJ, Coucke PJ, Santos-Cortez RLP, Spritz RA, Leal SM, Ahmad W (2017). Sequence Variants in Nine Different Genes Underlying Rare Skin Disorders in Ten Consanguineous Families. International Journal of Dermatology 56: 1406–1413. 7. Mehmood S, Mahmood A, Noor Z, Ahmad S, Jelani M, Tariq M, Rashid S, Ahmad W (2017). A novel homozygous sequence variant in the U2HR underlies Atrichia with papular lesions (APL) in two consanguineous families. (In Preparation)