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Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages

Thesis Info

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Author

Mehmood, Sabba

Program

PhD

Institute

Quaid-I-Azam University

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2018

Thesis Completion Status

Completed

Subject

Natural Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/9187/1/Sabba_Mehmood_Biochemistry_2018_QAU_HSR_21.06.2018.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725730568

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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)
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اماں ملی نہ ، ترستے رہے اماں کے لیے

اماں ملی نہ، ترستے رہے اماں کے لیے
تو زہر پی لیا تسکینِ جسم و جاں کے لیے

ہے میرے سر کو فقط تیرے نقشِ پا کی طلب
مری جبیں ہے ترے سنگِ آستاں کے لیے

خدا کرے کہ یہ ان آندھیوں سے بچ جائے
کہ تنکا تنکا جو رکھا ہے آشیاں کے لیے

نگاہِ بد سے بچے حسن کا وہ صدقہ دے
یہ مشورہ ہے مرا میرے مہرباں کے لیے

وہ ایک ایک مسافر نگاہ میں رکھے
بہت ضروری ہے یہ میرِ کارواں کے لیے

غم حیات کا سورج ہے سر پہ تو کیا غم
کسی کی یاد ہی کافی ہے سائباں کے لیے

چمن کو چھوڑ کے جانے لگے ہیں تائبؔ جی
قسم خدا کی یہ مژدہ ہے باغباں کے لیے

توضیح اصطلاحات فقہیہ: بذل المجہود کا مطالعہ و تجزیہ

Istilahat-e-fiqhia (Juristic terms) is of vital importance in understanding the exact meaning of the Islamic injunctions. Hadith Commentators, therefore, in their Hadith commentaries, ardently explain these terms literally as well as idiomatically. The present article, with the said perspective, studies Bazl al-Majhud fi Hall Sunan Abi Dawud, a multi-voluminous Arabic commentary of classical hadith corps Sunan Abi Dawud by renowned hadith scholar Moulana Khalil Ahmad Saharanpuri. It discovers that Moulana Saharanpuri elucidates the juristic terms with all the methods adopted by the experts of Ilm Lughat, Ilm Gharib al-Hadith, etc. He, in his elucidation, not only gives the inquiries of the experts but also evaluates them and gives his observations. However in some places he just copies the experts and doesn’t comment.

الکامات العربیۃ العربیۃ المشقدمۃ فی اللغۃ البولندیۃ

It is a common matter among many languages of the world that a language has an influence on one another, the same as phenomenon of linguistic borrowings is present in all languages and will be as long as different languages and contacts, direct or indirect, between their speakers exist. The term of "linguistic borrowing", according to linguists, means borrowing a word from a donor language, adaptation of this word and incorporating it into a recipient language. Therefore, in Polish language we find 845 words which have been borrowed from Arabic and entered into Polish language indirectly through other languages, such as: French, Spanish or Turkish, or directly through contacts between Arabs and Poles. At first glance at history of Poland and the Arab world it seems there is no cultural or linguistic link between them, nevertheless, in Polish language there are many lexical borrowings from Arabic which have been incorporated since 14th century through trade contacts, wars and settlement of Tatars in Poland. The research study which examines the link between these two languages is very rare due to Poles' lack of proficiency in Arabic, as well as Arabs' lack of proficiency in Polish. That is why, the need of creating a scientific research that describes the process of lexical borrowings from Arabic to Polish language, presents examples of such borrowings and explains the way of their entry into Polish, emerged in my mind. I believe that this research study titled "Arabic words used in Polish language (analytical and semantic study)" is going to be useful for Arab readers to make them realize the link between both languages, as well as it is going to be beneficial for linguists and researchers from both cultures and helpful for students of Arabic and Polish language in understanding the effect which Arabic had on forming Polish language. Linguists of Polish language do not take the issue of Arabic words used in Polish very often. The main Polish linguist who put a lot of effort into examining this topic in detail is Dr. Waclaw Przemyslaw Turek, the orientalist of Jagiellonski. University in Cracow, Poland. He wrote few articles about the adaptation of words borrowed from Arabic and incorporated into Polish language and a dictionary called "Slownik zapoZyczen pochodzenia arabskiego w polszczyinie". (Translation: Dictionary of Arabic loanwords used in Polish language) which is the main source of information on this particular topic in my research. This research study examines the words which have been borrowed from Arabic and are used till now in Polish language in an analytical and semantic way, presents the direct or indirect way of their entry into Polish, shows examples of lexical borrowings from Arabic into Polish with the indication of an Arabic origin word and explains the historical aspect of an adaptation of the borrowed word if known.