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Moecular and Genetic Insights On MOECULAR AND GENETIC INSIGHTS ON OCULOCUTANEOUS ALBINISM A thesis submitted to Bahauddin Zakariya University In Partial Fulfillment of the Requirement for the Degree of DOCTOR OF PHILOSOPHY IN MOLECULAR BIOLOGY & BIOTECHNOLOGY By TASLEEM KAUSAR September 2013 INSTITUTE OF MOLECULAR BIOLOGY AND BIOTECHNOLOGY BAHAUDDIN ZAKARIYA UNIVERSITY MULTAN, PAKISTAN I lovingly Dedicate To My FAMILY For their endless support, love and encouragement TABLE OF CONTENTS Title Page No. Dedication i Certificate from the Supervisor ii Supervisory Board iii Contents vi List of Tables vii List of Figures vii Acknowledgements xi Summery xii CHAPTER: 1 LITERATURE REVIEW 01 Section 1: Brief overview of Albinism 01 1.1 Brief overview of albinism 01 1.2 Inheritance pattern 01 1.2.1 Dominant OCA 02 1.2.2 Recessive OCA 02 1.2.3 X-linked recessive inheritance 02 1.3 Types of Oculocutaneous Albinism 02 1.4 Risk Factors 07 1.5 Clinical description 07 1.6 Symptoms 08 1.6.1 General Signs and Symptoms 08 1.6.2 Clinical presentation of various types of OCA 09 1.7 Diagnostic methods 11 1.7.1 Prenatal DNA testing 11 1.8 Complications 12 1.9 Melanin 13 1.9.1 Melanin localization in the cell 14 1.9.2 Types of Melanin 14 1.9.3 Stages of melanin synthesis 14 1.9.4 Melanin physiology 15 1.9.5 Hormone regulation 16 1.9.6 Melanin synthesis pathway 16 1.9.7 Tyrosinase enzyme 17 Section 2: Molecular and genetic characterization of OCA 18 1.10 Historic Overview 18 1.11 Epidemiology 19 1.12 Molecular description of OCA types 20 1.13 Syndromes associated with OCA 23 1.13.1 Hermansky–Pudlak syndrome 23 1.13.2 Chediak–Higashi syndrome 23 1.13.3 Griscelli syndrome 24 1.13.4 Prader-Willi and Angelman Syndromes 24 1.13.5 Waardenburg syndrome 25 1.13.6 Elejalde syndrome 25 CHAPTER: 2 MATERIAL AND METHODS 26 2.1 Approval of the study from Institutional Review Board 26 2.2 Identification, Enrollment and Clinical Assessment 26 2.3 DNA extraction by non-organic method 26 2.4 Screening of OCA genes by Sequencing 27 2.5 Generation of mini gene constructs 30 2.6 Transformation Protocol 33 2.6.1 Transfection of Mini Gene constructs 34 2.6.2 Transfection by Lipofectamine 2000 35 2.6.3 Transfection by Fugene HD 36 2.7 Reverse Transcription of RNA into 1st strand cDNA 37 2.8 Fluorescently Tagged Expression Constructs 38 2.9 Performing the TOPO® Cloning Reaction 38 2.9.1 Site Directed Mutagenesis 39 2.9.2 Transformation of XL10-Gold Ultracompetent Cells 39 2.10 Staining after transfection for Imaging 40 2.11 Protein isolation from transfected cells 41 2.12 Western Blot 41 2.13 Linkage analysis 42 2.13.1 Genome Wide Scan for Identification of New Loci 42 2.13.2 Linkage analysis 43 CHAPTER: 3 RESULTS 45 Overview of OCA1 results 45 OCA Families segregating TYR mutant alleles 45 3.1 PKAB074 46 3.2 PKAB001 and PKAB065 47 3.3 PKAB103 49 3.4 PKAB109 51 3.5 PKAB153 52 3.6 PKAB073 and PKAB078 53 3.7 PKAB057 and PKAB155 54 3.8 Temperature dependent retention of melanocytes 56 CHAPTER: 4 RESULTS 62 Overview of OCA2 results 62 4.1 PKAB058 and PKAB072 62 4.2 PKAB052, 054, 055, 067, and 101 64 4.3 PKAB063 67 4.4 PKAB063 69 4.5 PKAB071 70 4.6 PKAB060, 068, 079, 151, 152 71 CHAPTER: 5 OCA5 RESULTS 81 5.1 Family PKAB080 81 CHAPTER: 6 DISCUSSION 89 CHAPTER: 7 REFERENCES 93 SUPPLEMENTAL LIST OF TABLES Table Number Page No. Table 1.1: Proteins involved In OCA along with their probable functions 04 Table 1.2: Phenotypic presentation of different types of OCA 10 Table 3.1: Clinical assessment of the OCA1 affected individuals 60 Table 3.2: Mutant alleles of TYR found in ten Pakistani families 61 Table 4.1: Clinical assessment of the OCA2 affected individuals 77 Table 4.2: Mutations of OCA2 segregating in Pakistani families 79 Table 5.1: Clinical assessment of the family PKAB80 83 Table 5.2: Hematological assessment of the family PKAB80 84 Table 5.3: Multipoint LOD for family PKAB080 86 Table 5.4: SNP genotyping data on chromosome 14 for PKAB80 87 LIST OF FIGURES Figure 1.6 Iris transillumination in albinos 08 Figure 1.10 Schematic presentation of melanin synthesis pathway 18 Figure 3.1.1a Pedigree of the family PKAB074 46 Figure 3.1.1b Photograph of the proband of family PKAB074 46 Figure 3.1.2a Sequencing chromatograms for a mutation c.62C>T 47 Figure 3.1.2b ClustalW alignment of amino acid residue of Tyrosinase 47 Figure 3.2.1a Pedigree of the family PKAB001 48 Figure 3.2.1b Photograph of the proband of the family PKAB001 48 Figure 3.2.2a Pedigree of the family PKAB065 48 Figure 3.2.2b Photograph of the proband of the family PKAB065 48 Figure 3.2.3a: Chromatograms indicating a mutation c.104T>C 49 Figure 3.2.3b ClustalW alignment of amino acid residue of Tyrosinase 49 Figure 3.3.1a Pedigree of the family PKAB103 50 Figure 3.3.1b Photograph of the proband of the family PKAB103 50 Figure 3.3.2a Chromatograms indicating a mutation c.1321T>C 51 Figure 3.3.2b ClustalW alignment of amino acid residue of Tyrosinase 51 Figure 3.4.1a Pedigree of the family PKAB109 51 Figure 3.4.1b Photograph of the proband of the family PKAB109 51 Figure 3.5.1a Pedigree of the family PKAB153 52 Figure 3.5.1b Photograph of the proband of the family PKAB153 52 Figure 3.6.1a Pedigree of the family PKAB073 53 Figure 3.6.1b Photograph of the albino of the family PKAB073 53 Figure 3.6.2a Pedigree of the family PKAB078 54 Figure 3.6.2b Photograph of the albino of the family PKAB078 54 Figure 3.7.1a Pedigree of the family PKAB057 55 Figure 3.7.1b Photograph of the albino of the family PKAB057 55 Figure 3.7.2a Pedigree of the family PKAB155 55 Figure 3.7.2b Photograph of the albino of the family PKAB155 55 Figure 3.8.1 Subcellular distribution of wild-type and mutant tyrosinase 58 proteins grown at 37°C Figure 3.8.2 Subcellular distribution of wild-type and mutant tyrosinase 59 proteins grown at 31°C. Figure 4.1.1a Pedigree of the family PKAB058 63 Figure 4.1.1b Photograph of the proband of family PKAB058 63 Figure 4.1.2a Pedigree of the family PKAB072 63 Figure 4.1.2b Photograph of the affected individual of family PKAB072 63 Figure 4.2.1a Pedigree of the family PKAB052 64 Figure 4.2.1b Photograph of the affected individual of family PKAB052 64 Figure 4.2.2a Pedigree of the family PKAB054 65 Figure 4.2.2b Photograph of the affected individual of family PKAB054 65 Figure 4.2.3a Pedigree of the family PKAB055 65 Figure 4.2.3b Photograph of the affected individual of family PKAB055 65 Figure 4.2.4a Pedigree of the family PKAB067 66 Figure 4.2.4b Photograph of the proband of the family PKAB067 66 Figure 4.2.5a Pedigree of the family PKAB101 66 Figure 4.2.5b Photograph of the affected individual of family PKAB101 66 Figure 4.2.6a Sequencing chromatograms indicating a homozygous 67 transversion mutation c.1456G>T Figure 4.2.6b ClustalW alignment of amino acid residue of OCA2 67 Figure 4.3.1a: Pedigree of the family PKAB063 68 Figure 4.3.1b Photograph of the affected individual of family PKAB063 68 Figure 4.3.2a Sequencing chromatograms indicating a homozygous 69 transition mutation c.1580T>G Figure 4.3.2b ClustalW alignment of amino acid residue of OCA2 69 Figure 4.4.a Sequencing chromatograms indicating a homozygous 70 transition mutation c.954G>A Figure 4.4.1b ClustalW alignment of amino acid residue of OCA2 70 Figure 4.5.1a Pedigree of the family PKAB071 71 Figure 4.5.1b Photograph of the affected individual of family PKAB071 71 Figure 4.6.1a Pedigree of the family PKAB060 72 Figure 4.6.1b Photograph of the affected individual of family PKAB060 72 Figure 4.6.2a Pedigree of the family PKAB068 72 Figure 4.6.2b Photograph of the affected individual of family PKAB068 72 Figure 4.6.3a Pedigree of the family PKAB079 73 Figure 4.6.3b: Photograph of the affected individual of family PKAB079 73 Figure 4.6.4a Pedigree of the family PKAB151 73 Figure 4.6.4b Photograph of the affected individual of family PKAB151 73 Figure 4.6.5a Pedigree of the family PKAB152 74 Figure 4.6.5b Photograph of the affected individual of family PKAB152 74 Figure 4.6.6a Electropherograms of amplimers from genomic DNA 74 Figure 4.6.7a To determine the effect of the c.1045-15T>G mutation on 76 splicing, exon 10, an in vitro splicing assay. Figure 4.6.7b Gel image for the skipping of exon 10 from mutant construct 76 Figure 4.6.8a Human OCA2 isoforms with and without exon 10 76 Figure 4.6.8b RT-PCR for OCA2 transcript including exon 10 76 Figure 4.7: Summary of OCA known Mutations 95 Figure 4.8: Map of the Punjab province of Pakistan 99 Figure 5.1: Pedigree of the family PKAB080 100 Figure 5.2: Photographs of the affected individual of Family PKAB080 101 Figure 5.3: OCA5 linkage interval in family PKAB080 108 ACKNOWLEDGEMENTS All admirations and appreciations are for Almighty Allah, the most merciful and courteous, Who gave me courage to complete this research work.
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