مرثیہ حضرت شاہ محمد یونس صابری سرکار
( آستانہ عالیہ صابریہ ملتان شریف)
تیرا ہے احسان زمانے تھے بابا یونس لکھ ہزار
تیرا قرض ادا نہ ہو سکیا جہڑا ویکھیا سی تساں پہلی وار
اساں خوشیاں دے وچ بھل گئے
تہاڈے باجھوں سوہنیا رل گئے
تساں چھوڑا سانوں جل گئے
اسیں روندے پئے ہاں زار و نزار
در تیرے آکے قرار ملے
تیرے جیا نہ کدھرے پیار ملے
نہ ایہہ جیا کوئی وفادار ملے
گلی کوچہ ڈھونڈیا ہر بازار
کوئی ایڈا قاصد آیا جہدے اگے پیش نہ جاندی اے
مرن توں پہلے مرگئے انہا نوں موت کدے نہ آندی اے
کم ویکھ قضاء قدر دے بناں سجناں سنج ہو جاندی اے
سنجی پئی حویلی سانوں دسدا نہ سوہنا یار
تساں چھڑ کے سانوں ہے کتھے ڈیرا لایا
اساں روندے نیر وہاندے رہے
تہاڈے ہجر فراق اندر اسان رورو ہوش گنوایا
سوہنے مکھ نورانی والی سانوں جھلک دکھا ہک وار
تہاڈے باغ باغیچے تے پھل بوٹے پئے مہکدے ہر ہر جائیں
محفل خانیاں تھیں ذکر اذکار دیاں پیئاں ہون بلند صدائیں
جہڑی راہ وکھالی اسی ٹر دے اسے راہیں
پر تہاڈی جدوں یا دستاندی نین ہوجاندے اشکبار
قادری سائیںؔ یونس بابا جی ٹرگئے پر یاد انہاندی ریہہ گئی
چار چوفیرے پین بھلیکھے پر دل وچ صورت بہہ گئی
ایڈا دکھ وچھوڑے والا نال صبر دے جندڑی سہہ گئی
وچھڑے یار نہ بھلدے بھاویں گزرن سال ہزار
The Holy Qur’ān is a complete code of life or system of life for whole humanity. It gives complete guidance for human life from birth to death and for eternal life as well. The Qur’ān were the only book that changed the lives of the companions of Prophet Muhammad (ﷺ). And they became the most successful persons of the world. They ruled over three continents successfully with the guidance mentioned in Holy Quran. Today, we must adopt the guidance of Holy Qur’ān to change the humanity. In his thesis we addressed all aspects of human life including beliefs, modes of worship and customs of individual life, and also provided the guidance about the collective aspects of life, such as the economic aspects, as well as full instructions of political system and social aspect as well. So, counter the transcend world and get the eternal peace, success, and tranquility through Holy Quran.
Genetic defects in the complex processes of embryonic development of the skeleton and its postnatal maintenance result in different types of clinically diverse and genetically heterogeneous skeletal disorders. This presents a diagnostic challenge because of their nonspecific presentation, variable clinical features, highly overlapping phenotypes and lack of recognition as a discrete clinical entity. The research work, presented in this dissertation, describes clinical and molecular investigations of fourteen families (A-N) segregating various forms of skeletal disorders in autosomal recessive pattern. Clinical examinations were performed at local Government hospitals. Blood samples were collected from both affected and unaffected members of the families. Genomic DNA, extracted from the blood samples, was used for microsatellite and SNP based genetic mapping and whole exome and chain termination sequencing. Clinical features, observed in affected members of six families (A-F), were analogous to a condition named as mucopolysaccharidosis. Linkage in these families was established to chromosome 16q24.3 harboring GALNS gene. Sanger sequencing revealed two novels (p.Phe216Ser, p.Glu121Argfs*37) and two previously reported mutations (p.Pro420Arg, p.Arg386Cys) in GALNS gene in the six families. In silico analysis predicted that the missense mutations affect structure and function of the GALNS protein. Clinical and radiographic examinations of affected members in three families (G-I) underscored the manifestations of acromesomelic dysplasia. Microsatellite based genotyping followed by sequence analysis of the NPR2 gene identified three novel missense mutations (p.Arg749Trp, p.Arg601Ser, p.Leu314Arg) in the families. Human genome scan using SNP microarray followed by exome sequencing discovered a potentially casual frameshift mutation (c.594-595insT; p.Gln198Thrfs*21) in a novel gene KIAA0825 in the family J segregating post-axial polydactyly in an autosomal recessive manner. Affected individuals in family K exhibited peculiar clinical features including post axial polydactyly, speech impairment, hearing impairment of variable degree and proportionate short stature. This condition represented mild form of Joubert Abstract Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders XVIII syndrome. Whole exome sequencing in the family revealed a novel in-frame deletion mutation (c.1115-1117delCCT; p.Ser372del) in the MKS1 gene. In silico analysis revealed that Ser372 residue resides in the “B9” interacting region of the MKS1 protein and inframe mutation (p.Ser372del) causes alteration in the conformation of mutant protein with two extra α helixes. The present study described three families (L-N) with split hand/foot malformations. In two families (L, M), genetic mapping followed by Sanger sequencing detected a novel frameshift mutation (c.300-306dupAGGGCGG; p.Leu103Argfs*52) in the WNT10B gene. In the third family (N), whole exome sequencing accompanied by SNP microarray, identified six nucleotides duplication (c.217-222dupCACCCG; p.His73_Pro74dup) in a novel causative gene HOXD8. The work presented in the dissertation resulted in the following publications. 1. Irfanullah, Saadullah Khan, Imran Ullah, C. Arnoud Meijer, Marlies Laurense Bik, Johan T den Dunnen, Claudia AL Ruivenkamp, Marriët JTV Hoffer, Gijs WE Santen, Wasim Ahmad (2016). Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: expanding the phenotypic spectrum of MKS1-related ciliopathies. American Journal of Medical Genetics Part A 9999A:1–5 2. Irfanullah, Muhammad Umair, Saadullah Khan, Wasim Ahmad (2015). Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families. Annals of Human Genetics 79: 238–244 3. Abdul Aziz, Irfanullah, Saadullah khan, Faridullah khan zimri, Noor Muhammad, Sajid Rashid, Wasim Ahmad (2014). Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families. Gene 534: 265–271. 4. Irfanullah, Abdul Nasir, Sarmad Mahmood, Sohail Ahmed, Muhammad Ikram Ullah, Asmat Ullah, Abdul Aziz, Syed Irfan Raza, Khadim Shah, Saadullah Khan, Muhammad Jawad Hassan, Wasim Ahmad (2016). Identification and in silico analysis of GALNS mutations causing Morquio A syndrome in eight consanguineous families. Turkish Journal of Biology: DOI:10.3906/biy-1607-81 Abstract Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders XIX 5. Asmat Ullah, Ajab Gul, Muhammad Umair, Irfanullah, Abdul Wali, Farooq Ahmad, Abdul Aziz, Wasim Ahmad (2017). Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation. Genetics and Molecular Biology (Submitted) 6. Irfanullah, Muhammad Ansar, Saadullah Khan, Abdul Aziz, Wasim Ahmad. Exome sequencing revealed a novel gene KIAA0825 underlying autosomal recessive postaxial polydactyly (In Preparation). 7. Irfanullah, Saadullah Khan, Maaike Verschuren, Marlies Laurense Bik, Johan T den Dunnen, Claudia AL Ruivenkamp, Marriët JTV Hoffer, Gijs WE Santen, Wasim Ahmad. Human HOXD8 is a novel candidate gene causing autosomal recessive split hand foot malformation in a large Pakistani consanguineous family (In Preparation) 8. Irfanullah, Syed Zohaib Tayyed Gilani, Saadullah Khan, Wasim Ahmad. Homozygous mutations in NPR2 gene underlying Acromesomelic dysplasia in Pakistani families (In preparation)