Genome mappingin Human Hereditary Polydactyly

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Genome mappingin Human Hereditary Polydactyly
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   i Genome mapping in Human Hereditary Polydactyly Submitted to: Dr.Mohammad Tahir Waheed Submitted by: Mehmand khan Programme: M.Phil Semester: 1st Department: Biochemistry   QAU Islamabad     ii Contents Abstract  ...................................................................................... Error! Bookmark not defined.   Chapter 1  ................................................................................... Error! Bookmark not defined.   1. Introduction  ....................................................................... Error! Bookmark not defined.   1.1. Human Skeletal Disorders  ............................................ Error! Bookmark not defined.   1.3.1 Polydactyly ................................................................ Error! Bookmark not defined.   1.3.2 Polydactyly classification  ......................................... Error! Bookmark not defined.   1.3.2.2 Postaxial polydactyly (PAP )  ................................. Error! Bookmark not defined.   1.3.2.3 Complex types of polydactyly  .............................. Error! Bookmark not defined.   1.3.2.4 Mirror-image polydactyly: (MIP)  ....................... Error! Bookmark not defined.   1.4 Aims and objectives  ........................................................ Error! Bookmark not defined.   Chapter 2  ................................................................................... Error! Bookmark not defined.   2. Materials and Methods  ..................................................... Error! Bookmark not defined.   2.1 Pedigree Construction  ................................................ Error! Bookmark not defined.   2.2 Blood Sample Collection  ............................................. Error! Bookmark not defined.   2.3 Genomic DNA Extraction  .......................................... Error! Bookmark not defined.   2.4 Agarose Gel Electrophoresis  ...................................... Error! Bookmark not defined.   2.5 Genotyping and linkage analysis  ............................... Error! Bookmark not defined.   2.6 Polymerase Chain Reaction (PCR)  ........................... Error! Bookmark not defined.   2.8 Plan B  ........................................................................... Error! Bookmark not defined.   2.9 Timeline graph  ............................................................ Error! Bookmark not defined.   Chapter 3  ................................................................................... Error! Bookmark not defined.   3. Expected results  ................................................................ Error! Bookmark not defined.   Chapter 4  ................................................................................... Error! Bookmark not defined.   4. Discussion /Conclusion  ..................................................... Error! Bookmark not defined.   Chapter 5  ................................................................................... Error! Bookmark not defined.   REFERENCES   Error! Bookmark not defined.     iii Abstract Skeletal dysplasia’s  are phenotypically and genotypically heterogenous group of congenital disorders. Polydactyly is a type of skeletal malformations characterized by extra digits in limbs. The phenotypic spectrum ranges from preaxial polydactyly to  post axial polydactyly, depanding upon gene(s) involved. Uptill now mutations in  ZNF141, GLI-3 and  ZRS/SHH have been reported   for various forms of polydactyly. The main aim of present research work is to elucidate phenotypic and genotypic correlation by linkage analysis of reported genes in consanguineous families of Pakistan using microsatellite markers. After confirmed linkage, the specific gene(s) will be Sanger sequenced to analyse mutation. Analysis of sequencing results may have two possible results; there may be a mutation in reported gene(s) or mutation in regulatory sequences or another novel gene(s) is involved in disease phenotype. Keywords : Polydactyly,  ZNF141, GLI3, ZRS/SHH, Linkage, Sanger sequencing.   1 Chapter 1 1. Introduction Vertebrate endoskeleton is a rigid frame work of complex external and internal structure and function to support and protect the body, and produce white and red  blood cells. Skeletogenesis begins at the 4 th  week of gasrtrulation in which the mesenchymal cells migrate to specific locations in the body, and accomplish the skeleton formation. The embryonic cells further differentiate into three types of cells including chondrocytes, osteoclasts and osteoblasts. Chondrocytes finally differentiate into cartilage while osteoclasts and osteoblasts into bone. The skeletogenic cells then starts osteogenesis (formation of bones) by two processes: intramembranous ossification (direct conversion of osteoblasts to bone matrix) and endochondral ossification (formation of cartilage template by chondrocytes that is subsequently replaced by bone). The processes of development, differentiation and organ formation are governed by various transcription factors, growth factors, hormones and their intercellular signals (Karsenty and Wagner, 2002; Tuan, 2003). Defects in any of the step of skeletal development or growth can give rise to skeletal anomalies. 1.1. Human Skeletal Disorders  Human skeletal dysplasias are genetically heterogeneous group of disorders that results from errors in bone, cartilage and joint development. They are characterized by abnormalities in patterning, differentiation, linear growth and maintenance of the human skeleton. A complex series of signaling cascades, including the FGF, BMP, TGF β, WNT, Notch, Hedgehog pathways, are essential for proper skeletogenesis. Human skeletal dysplasias are often a consequence of a primary or secondary dysregulation of these pathways. Although individually rare, the overall birth incidence is estimated to be 1/5000 live births (Orioli et al  ., 1986). Many limb skeleton disorders include abnormalities of patterning of hands and feet like polydactyly, syndactyly, clinodactyly, ectrodactyly/SHFM and bracydactyly.
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