Search or add a thesis

Advanced Search (Beta)
Home > Identification of Genes Involved in Causing Diseases of Ectodermal Appendages

Identification of Genes Involved in Causing Diseases of Ectodermal Appendages

Thesis Info

Access Option

External Link

Author

Naz, Gul

Program

PhD

Institute

Quaid-I-Azam University

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2012

Thesis Completion Status

Completed

Subject

Natural Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/handle/123456789/1824

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726396292

Similar


The ectoderm is the outermost layer of the developing embryo that gives rise to epidermis and its appendages. Ectodermal appendages share a common developmental program that relies on extensive coalition amongst epithelia and nearby mesenchyme. The genetic pathways involved in the regulation of appendage development are widely conserved between species and different appendages. In the present investigation nine consanguineous, multigeneration families (A-I) segregating autosomal recessive hereditary disorders of ectodermal appendages were ascertained from different zones of Pakistan. Homozygosity mapping via polymorphic microsatellite markers was used to elucidate the gene defect in eight families while for one family microarray technology was used. In family A, affected individuals showed characteristic clinical features of hereditary hypotrichosis including sparse hair on the scalp and rest of the body. Interestingly, eyebrows and eyelashes were not affected in any of the affected individuals. Human genome scan using 400 highly polymorphic microsatellite markers mapped the disease locus to a large region on chromosome 10. This novel locus maps to 29.18 cM (28.50 Mb) region, flanked by markers D10S538 and D10S2327 on chromosome 10q11.23–q22.3. A maximum multipoint LOD score of 3.26 was obtained at recombination fraction zero with several markers in this region. Exons and splice-junction sites of five putative candidate genes (DKK1, MYST4, ZMYND17, P4HA1, ZNF365), located in the linkage interval, were sequenced but were negative for functional sequence variants and therefore their involvement in causing hypotrichosis phenotype at the present novel locus is not supported. In family B, affected individuals showed clinical features of autosomal recessive hypotrichosis (LAH2) including thin fragile hair on scalp, sparse to absent eyebrows and eyelashes, and sparse hair on rest of the body. Morphological inspection of hairs by light microscopy did not reveal any nodes or constriction. Histopathological examination of the biopsy showed complete absence of normal hair follicle structures. Genotyping data showed linkage of the family to LIPH gene on chromosome 3q27.3. Sequence analysis of LIPH gene revealed a novel homozygous missense mutation (c.2T>C, p.M1T) in all the affected individuals.Three families (C, D, E) showed archetypal clinical features of autosomal recessive hypotrichosis (LAH3). The patients showed sparse to absent twisted scalp hair, sparse eyebrows and eyelashes, sparse axillary and body hair. Genotyping data showed linkage of the families to LPAR6 gene on chromosome 13q14.2. Sequence analysis of the LPAR6 gene revealed one novel homozygous missense mutation (c.8G>C, p.S3T) in family C, and two previously reported mutations (c.436G>A, p.G146R; c.69insCATG, p.24insHfsX29) in the other two families (D and E). In family F, affected individuals showed clinical phenotypes of autosomal recessive hypotrichosis (LAH1). Out of 12 individuals over four generations, only two females were found to be affected. They showed complete loss of scalp hairs and eyebrows, however very thin eyelashes were present. Genotyping data showed linkage of the family to desmoglein and desmocollin gene cluster on chromosome 18q12.1. Sequence analysis of six candidate genes (DSG1-4, DSC1, DSC3) failed to detect any functional sequence aberration, that could be responsible for the disease phenotype in this family. Family G showed clinical features of atrichia with papular lesions. Patients showed complete hair loss of scalp, absent eyebrows and eyelashes, loss of axillary and pubic hair. Genotyping results showed linkage of the family to human hairless gene (HR) located on chromosome 8p21.3. Sequence analysis of the coding exons and splice junction sites of the HR and its upstream region (U2HR) failed to detect any functional sequence variant. In family H, affected individuals showed isolated nail dysplasia phenotype; thickening and hyperpigmentation of all finger- and toenails that become claw like around teenage. Genome scan using Illumina‟s Human 660W-quad chip was performed that showed a single homozygous region on chromosome 8q22.3. In parallel sequence analysis of five selected candidate genes (ATP6V1C1, BAALC, CTHRC1, KLF10, FZD6) in the linked region revealed the disease causing homozygous nonsense mutation (c.1750G>T, p.E584X) in the frizzled 6 (FZD6) gene, a member of Wnt signaling pathway. Expression analyses in nail sections showed a strong expression of FZD6 in the ventral nail matrix and to lesser extent, the nail bed. Manuscript describing “FZD6 encoding the Wnt receptor frizzled-6 is mutated in autosomal recessive nail dysplasia” was submitted for publication to American Journal of Human Genetics. However, before the manuscript could be sent for review, another group published FZD6 mutation paper in the same journal. Now the present manuscript has been submitted for publication to British Journal of Dermatology.In family I, affected individuals showed clinical features of ectodermal dysplasia (ED) of hair and nail type; characterized by total or partial hair loss and dystrophy of finger- and toenails since birth. Genotyping data showed linkage of the family to type II keratin gene cluster on chromosome 12p11.22–12q14.1. This region corresponds to 30.92 Mb (22.34 cM) according to the sequenced based physical map (Build 36.2) of the human genome and flanked by markers D12S1631 and D12S298. A maximum two-point LOD score of 3.59 was obtained with three markers while maximum multipoint LOD score exceeding 4.0 was obtained with nine markers along the disease interval at recombination fraction zero. KRT85 has previously been reported as a causative gene for ED of hair and nail type at chromosome 12q13.13. KRT85 along with twelve other genes (KRT81, KRT82, KRT83, KRT84, KRT86, KRT6C, KRT71, KRT72, KRT74, KRT75, KRT78, WNT10B) were sequenced. However sequence analysis failed to detect any functional sequence variants.
Loading...
Loading...

Similar Books

Loading...

Similar Chapters

Loading...

Similar News

Loading...

Similar Articles

Loading...

Similar Article Headings

Loading...

احترامِ آدمیت

احترام آدمیت
اس کائنات ِرنگ و بو میں ہر چیز اپنی شناخت اور پہچان رکھتی ہے، اپنے وجود کے اظہار کے لیے اس کی کوئی نہ کوئی شناخت ہے سورج کی شناخت یہ ہے کہ وہ مشرق سے نکلتا ہے اور مغرب میں غروب ہو جاتا ہے، ستاروں کی شناخت یہ ہے کہ وہ رات کو آسمان پر درخشاں ہوتے ہیں۔ پہاڑوں کی شناخت اور پہچان یہ ہے کہ دور سے دکھائی دیتے ہیں اور بلندو بالا ہوتے ہیں۔ اسی طرح پھول کی پہچان ہے کہ وہ خوشبوفراہم کرتا ہے اور اپنے اردگرد کے ماحول کو معطر اور خوشبودار رکھتا ہے۔ اسی طرح مسلمان کی بھی ایک پہچان ہے وہ یہ کہ اس کے ہاتھ اور زبان سے دیگر مسلمان محفوظ رہتے ہیں۔ وہ کسی کو گزند نہیں پہنچا تا کسی کو تکلیف پہنچانا اس کو ناگوار گزرتا ہے۔ کسی کی پریشانی وہ اپنی پریشانی سمجھتا ہے۔ تو بس اس بات کا قائل ہوتا ہے کہ آدمی اور انسان کا احترام کیا جائے اور اس کے حفظ مراتب کا خیال رکھا جائے۔ قرآنِ پاک میں بھی انسان کے ساتھ حسنِ سلوک اور رواداری کی تلقین آئی ہے۔ ارشادِ باری تعالیٰ ہے:
’’لوگوں کے ساتھ احسن طریقے سے گفتگو کر یں، حسن سلوک سے پیش آئیں ‘‘
اسلام کی جملہ تعلیمات احترامِ آدمیت کی تلقین کرتی ہیں نماز ایک ایسی عبادت ہے جس کو ہم دن میں پانچ مرتبہ ادا کرتے ہیں۔ اور اس میں بھی حکم ہے کہ جب مسجد میں نماز ادا کرنے کے لیے کوئی آئے خواہ وُہ لباس فاخرہ میں ملبوس ہو، خواہ وہ صاف مگر سادہ لباس زیب تن کئے ہوئے ہو۔ خواہ اس کا قد بڑا ہو، د بلا پتلا ہو یا لحیم شہیم ہو وہاں سب برابر ہیں۔ اور ایک ہی صف میں کھڑے ہوں گے امیر وغریب اور سرخ سفید...

مالكانہ تصرفات پر نفاذ حجر كے اسباب

Where Islam takes the protection of human life on first priority there it places the fluctuation and safety of one's property and ownership on the second priority_ Qura’nic Verses, sayings of the Prophet and civil and criminal juristic laws stress the protection of property__ The extravagancy, misuse, theft, robbery, usurpation, aleatory, deception and alike have been termed unfair means regarding the property. Besides, according to Muslim jurists there are some other elements, if not checked may lead to deterioration of property_ like disposition of property during immaturity, lunacy, drunkenness and inebriety, stupidity etc. In this connection Islamic Law introduces the rules of Hajr (interdiction) which ensure the sanction upon such a person found suffering from the above imperfection and forbids him to make disposition in his own property and terms it invalid for further legal effects. In juristic terminology such rules are called Hap (interdiction) .

Isolation and Characterization of Biologically Active Compounds from Selected Medicinal Plants

The main objective of this study was to discover new cancer chemopreventive and cytotoxic compounds from the natural sources to combat cancer. For the purpose, after an extensive survey based on the information gathered from local healers, six medicinally-important plants of Pakistan were selected for investigation. These plants included Euphorbia wallichii Hook F., Bergenia ciliata (Haw.) Sternb, Acer oblongifolium Hort. ex Dippel, Aster thomsonii C. B. Clarke, Opuntia dillenii (Ker Gawl) Haw. and Withania coagulans (Stocks) Dunal. For initial screening, total 59 extracts/fractions were prepared by using the different techniques including maceration, solvent-solvent extraction, flash column chromatography and solid phase extraction. All the extracts/fractions were tested for their anticancer and cancer chemopreventive activity by employing seven independent assays. Overall the results of the initial screening were very encouraging and led to the selection of the most potent plant material for further investigation. NFĸB activity plays a critical role in cancer development, progression and therapy and two of our samples from Withania coagulans demonstrated greater than 90% inhibition of TNF-α induced activity of NFĸB. Aromatase inhibitors are known to be effective for the treatment and prevention of breast cancer. One fraction from aerial parts of each plant, W. coagulans and Euphorbia wallichii, inhibited aromatase by 100% and 73%, respectively. Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) plays critical role in inflammation, cell survival and tumor development and progression. Five of our samples, one from aerial parts of E. wallichii, one from Aster thomsonii, and three from fruit bearing aerial parts of W. coagulans, inhibited NO production significantly in lipopolysaccharide activated macrophage RAW 264.7 cells as a marker of iNOS inhibitor. No extracts or fractions was deemed active in RXRE assay. DPPH free radical scavenger has potential use to scavenge oxygen free radicals, which are the product of normal cellular metabolism and can attack and produce endogenous DNA lesions leading to genotoxicity, mutation and cancer. A total of 25 extracts/fractions exhibited ≥ 70% scavenging at 200 μg/ml concentration in DPPH assay, among them 13 were from roots and aerial parts of E. wallichii, 5 from B. ciliata, 6 from A. oblongifolium and one from A. thomsonii. QR1 is measured as overall representative of the phase II enzymes. Phase xiii Abstract II enzymes are primarily responsible for the metabolic detoxification of chemical carcinogens and other harmful oxidants, leading to the protection of cells against redox cycling, oxidative stress, and carcinogenesis. Therefore, induction of QR1 at the tumor initiation stage is suggestive for cancer prevention potential. A total of 10 extracts/fractions demonstrated potent induction of QR1 in a cell-based assay with CD (concentration required to double the enzyme activity) <10 μg/ml among them one is from A. oblongifolium and 9 from W. coagulans. A total of 8 extracts and fractions showed cytotoxicity in an SRB assay against MCF-7, LU-1 and MDA-MB 231 cancer cell lines, among them 3 are from E. waliichii and 5 from the W. coagulans. The overall results suggested that W. coagulans might be the most promising plant for further studies as the extracts/fractions from this plant showed highest and significant activity in most of the assays. After the initial screening, W. coagulans was selected to pursue further for isolation and purification of the pharmacologically relevant compounds. For this purpose, total 10 kg dry weight of the W. coagulans aerial part was extracted, fractionated and subjected to biological evaluation in the above described assays to confirm the biological activities and to find the most active fractions. Active fractions were further processed through sequential bioactivity guided fractionation utilizing various chromatographic techniques, which led to isolation of 9 biologically active pure compounds. Structure elucidation of these compounds was carried by utilizing mass spectrometry (MS), one dimensional nuclear magnetic resonance (1D-NMR), and two dimensional nuclear magnetic resonance (2D-NMR) techniques. Structural elucidation showed that these compounds belong to a very important, biologically active and chemically distinct class of natural products known as “withanolides”. On the basis of existing reports and spectroscopic results it is concluded that out of these 9 compounds 3 are new and 6 are already known withanolides. This study is a contribution towards the exploration of new withanolides as well as their potential use in cancer chemopreventive and anticancer drug discovery.