اسلامی ریاست میں داخلی استحکام کے لیے مرکز اور صوبوں کے تعلقات

There is a dire need of an experienced and authoritative mechanism in the polity of Islām in order to run the affairs of the state in a benefiting manner. This mechanism divides the state into different regions and provinces so as to carry out the affairs of the state in an organized way. These provinces must be founded on some administrative basis, not on racial, lingual or regional grounds. It is necessary that these units are autonomous as far as authority and power is concerned. It will help eradicate parochial differences and strengthen integrity of a country. It is essential to keep up and safeguard the freedom and the rights of these units. We can get our desired objectives, if legal and constitutional safeguards are meted out to these administrative units of the state. According to ‘Allāmah Ibn Khaldūn’s point of view, it is imperative to strengthen a state instead of expanding it. There must be small but integrated autonomous units of the state. Such division helps these units to progress and prosper. The golden principle of power distribution is in vogue in all eras, although its structure has been different and varied. In this article, we are going to view the structure of distribution in the perspective in an Islamic state

Genetic Mapping and Mutation Analysis of Genes Causing Disorders of Human Ectodermal Appendages

The study, presented in the thesis, is an effort to explore genetic basis of disorders of ectodermal appendages in different ethnic populations living across Pakistan. Hereditary hypotrichosis and ectodermal dysplasias are large, complex and heterogeneous groups of heritable conditions characterized by congenital abnormalities of ectodermal appendages. They can broadly be characterized into two groups depending upon the absence (isolated) or presence (syndromic) of associated defects in other organ/organ systems. Discovery of genes responsible for these disorders is the key source of insight into the molecular mechanisms of development and differentiation of ectodermal appendages. Focus of the present study was to identify and characterize genes causing hereditary disorders of ectodermal appendages in fifteen families (A-O) of Pakistani origin. Eleven of these families (A-K) were segregating various types of hair loss disorders and four families (L-O) ectodermal dysplasias. Combination of various techniques including microsatellite and SNP genotyping, Sanger sequencing and exome sequence analysis assisted in establishing linkage and identifying disease causing variants in the families. Four families (A, B, C, D) with non-syndromic hair loss failed to show linkage to the known genes. Subsequently, three of them were subjected to whole-genome SNP genotyping. Human genome scan mapped a novel disease locus of 10.85 Mb on chromosome 2q31.1–q32.2 in family A. Sequencing of the three selected putative candidate genes (ITGA6, PRKRA, ATF2), mapped in the linkage interval, did not reveal any functional variant in the family. Family B showed linkage to chromosome 6p25.1–p23, and subsequently a novel variant (c.1493C>T; p.Pro498Leu) in the DSP gene was identified upon sequencing. Whole-genome SNP genotyping coupled with whole exome sequencing identified two compound heterozygous deletions, a novel (c.278_278delA; p.Lys93Argfs*9) and a previously reported (c.659_660delTA; p.Ile220Argfs*25), in the LIPH gene in family D. Genetic Mapping and Mutation Analysis of Genes Causing Disorders of Human Ectodermal Appendages xixAbstract Six families (E, F, G, H, I, J) with non-syndromic hair loss showed linkage to previously reported genes (LIPH, LPAR6, HR) involved in causing hypotrichosis. Linkage in four of these families (E, F, G, H) was established to the LIPH gene on chromosome 3q26.33–q27.3. Sequence analysis of the LIPH revealed a previously described deletion (c.659-660delTA; p.Ile220Argfs*25) in three families (F, G, H). However, sequence analysis failed to detect variant in the LIPH gene in family E. Haplotype analysis showed linkage of the family I to the LPAR6 gene on chromosome 13q14.11–q21.32. Sequence analysis of the gene revealed a previously described variant (c.562A>T; p.Ile188Phe) in the family. In the family J, linkage was established to the HR gene on chromosome 8p21.3. Sequencing of the gene revealed a previously reported variant (c.2070C>A; p.Cys690*). In the family K, segregating novel features associated with hair loss, exome sequence analysis led to the identification of a novel rare variant (c.898G>A; p.Glu300Lys) in ITGB6 gene that co-segregated with the phenotype in the family. Four families (L-O) showed features of different forms of ectodermal dysplasias. The family L showed features of pure hair and nail ectodermal dysplasia (PHNED). Haplotype analysis mapped the family to the previously reported locus on chromosome 12p13.11–q21.1. Three genes (KRT85, HOXC13, KRT74), known to cause PHNED lie in this region, were screened but found to be negative for any potential sequence variant. Haplotype analysis established linkage to the previously proposed locus on chromosome 4q32.3–q34.3 in family M segregating isolated form of congenital nail clubbing (ICNC). HPGD, a cause of ICNC, lies in this region, was sequenced but found to be negative for any potential variant. Genome-wide homozygosity mapping complimented with whole exome sequencing identified a previously reported variant (c.5314C>T; p.Arg1772Trp) in COL7A1 segregating autosomal recessive form of dystrophic epidermolysis bullosa (RDEB) in the family N. In family O, segregating variegate porphyria (VP), exome sequence analysis led to the identification of a previously described sequence variant (c.502C>T; p.Arg168Cys) in the PPOX gene that co-segregated with the disease.