سماحت اور رہبانیت: شاہ ولی اللہ کا موقف

The hall mark of Shah Waliullah has been advocate moderation and the communal spirit of Isla shuns worldly attitude and abhors rejection of the wor and offers a middle path. There is no extremism in Isla and Shah Wali Ullah has preached the same. The juris the Sufis and the Muhaddisseen have taken up a differe line of thinking regarding "Tassawwuf" --- yet th essential spirit of Islam is the path of moderation. T spiritualism and physical world has to be kept in balance— with moderation and balance. It is this aspect of Sha Waliullah's writings that has been highlighted in th article.

Molecular Characterization of Syndromic and Nonsyndromic Forms of Deafness Using Molecular Genetic Approaches

Hearing loss is a common neurosensory impairment, which has a significant genetic etiology. A hearing loss affects 1 in 1000 newborns and 1 in 300 children by the age of 4 years (Chang 2015). It has been estimated that 1% of almost 30,000 protein coding genes in human are associated with hearing phenotype (Friedman and Griffith 2003). The mechanism of hearing is not fully understood because of the challenges associated with studying inner ear architecture, but nonetheless some of the key genes encoding distinct mechanisms of hearing have been explored by using genetic tools. Recent studies in the field of human genetics have been influential in identifying some of the proteins underlying mechanisms essential for sound transduction, as for example, hair cells electromotility, mechanotransduction, development of inner and outer hair cells, and the molecular composition of the ribbon synapse. Using a genetic approach, this thesis research project explored novel genes involved in non-syndromic and syndromic forms of hearing loss. Participants from 85 families that are segregating moderate to severe degree of hearing loss are included in this study. The affected individuals from 85 different families were initially screened for mutations of GJB2 and HGF. Genetic variants of these two genes are common in the Pakistani population and there is only one protein-coding exon of GJB2 and two common intronic mutations of HGF which are easily sequenced for mutations. I have identified twenty five novel mutations in genes that have been associated with hearing loss and all of the identified novel mutations are predicted to be pathogenic according to multiple in silico tools and have an allele frequency less than 0.005%. Mutations of MYO15A, GJB2 and HGF are the three-major contributors to deafness in this cohort of eighty-five families. In this thesis research project, I have successfully utilized some of the latest techniques in genetics that includes Whole Exome Sequencing (WES), genome wide SNP genotyping, and Whole Genome Sequencing (WGS) and was able to identify novel genes involved in syndromic and non-syndromic forms of deafness. In family PKDF1400, I completed genome wide SNP genotyping of affected and unaffected individuals. Genotyping data revealed a significant linkage score on chromosome 19p13.2 that encompasses DFNB68 locus. Individuals from PKDF1400 were then subjected to WES and I identified a missense pathogenic variant of S1PR2 (p.Tyr140Cys). Sanger sequencing of the single nucleotide variant revealed co segregation with the phenotype in PKDF1400. This thesis project has contributed data in identifying a novel gene underlying DFNB68 form of deafness (Santos-Cortez et al. 2016). I also identified a variant of SGO2 that is necessary for fertility in a Perrault syndrome proband of family PKDF063, which was ascertained from Pakistan. Whole exome sequencing of affected and unaffected members of PKDF063 revealed a truncating mutation of SGO2 p.(Glu485Lysfs*5) associated with the proband’s infertility phenotype. This is the first report of an association of SGO2 with human infertility (Faridi et al. 2017). I was successful in identifying a rare truncating mutation in family PKDF461 using Whole genome sequencing. PKDF461 was ascertained as a family segregating non syndromic hearing loss. The family has significant linkage of deafness to the DFNB8/10 interval which was further narrowed after analyzing WGS data that revealed a novel nonsense mutation of KCNE1 (p.Tyr46*). Mutations of KCNE1 are associated with Jervell and Lange Nielson syndrome (JLNS2) but this is the first truncating mutation of this gene.Overall, this thesis research project has identified novel gene for human hearing and fertility and has expanded the genotype-phenotype spectrum associated with Perrault syndrome and Jervell and Lange Nielson syndrome. This study has contributed twenty five novel genetic variants in several different genes that are critical for normal auditory function. Overall, this research project utilized cutting-edge genomic technologies that have revealed molecular genetic explanations for hereditary hearing loss in human families and was successful in identifying novel genes for non-syndromic and syndromic forms of hearing loss.