I= GENETIC EPIDEMIOLOGY AND MOLECULAR STUDIES OF CONGENITAL BLINDNESS AT FAMILY LEVEL
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Title of Thesis
GENETIC EPIDEMIOLOGY AND MOLECULAR STUDIES OF CONGENITAL BLINDNESS AT FAMILY LEVEL

Author(s)
Farhat Jabeen
Institute/University/Department Details
Department of Biological Sciences/ Quaid-i-Azam University, Islamabad
Session
2004
Subject
Biological Sciences
Number of Pages
145
Keywords (Extracted from title, table of contents and abstract of thesis)
congenital blindness, eye disorders, leber’s congenital amaurosis, autosomal recessive lca, autosomal recessive macular degeneration, retinal degeneration, autosomal recessive hereditary fundus dystrophy, autosomal recessive retinitis pigmentosa sine pigmento, homozygosity autosomal recessive inheritance pattern

Abstract
The present study includes five families affected with congenital blindness from different areas of Pakistan. The aim of the present study was to obtain a base line information regarding the development of eye disorders in some Pakistani families at molecular level. Clinical assessment was obtained before carrying out linkage analysis at molecular level in these families.

Family-1 was designated as 3CBL and was diagnosed for Leber’s Congenital Amaurosis (LCA) with autosomal recessive mode of inheritance. The surname of the family was Abbasi. Their marriages were contracted both among cousins and distant relatives. The kindred spans on five generations. It consisted of 77 individuals out of which 62 were live and fifteen were dead at the time of study. Of these live members, thirteen members were affected including six females and seven males. Twenty nine individuals of the family were processed for molecular studies. These include 11 affected and 18 normal individuals. Of eleven blind individuals six were males and five females. The samples were further processed for genetic analysis at Biomedical and Genetic Engineering Division, KRL, Islamabad. Linkage analysis for known loci of autosomal recessive LCA loci was carried out. Significant linkage was found with LCA4 locus (17p13.1). Two point lod score analysis resulted in maximum lod score (Z max) of 4.75 for marker DI7S796 at θ=0.

Family-2 was designated as 4CBL also diagnosed for Leber’s Congenital Amaurosis (LCA) with autosomal recessive mode of inheritance. The surname of the family was Raja. The kindred spans on five generations. It consisted of 29 individuals out of which twelve were live and seventeen were dead at the time of study. Of these live members, five members were affected including two females and three males. For molecular studies peripheral blood was collected from seven individuals with informed consent of the family. These include four affected and three normal individuals. Linkage analysis for known loci of autosomal recessive LCA loci was carried out. Linkage was found with LCA4 locus (17p13.1). Two point lod score analysis resulted in maximum lod score (Z max) of 2.06 for marker D17S1832 at θ=0. This marker seems to be linked with disease region but due to less number of informative meioses this score is less than 3. And also the tightly linked marker for this region was unfortunately non-informative for this family.

Family-3 was designated as 7CBL and diagnosed for autosomal recessive macular degeneration. The surname of the family was Muslim Sheikh. Mostly consanguineous marriages were contracted within the kindred resulting in a higher number of affected individuals. The kindred spans on six generations and consists of 69 individuals, of which 48 were alive and 21 were dead at the time of study. Of these 48 live individuals 22 were affected, including 13 males and nine females. Twenty-eight members of this family were processed for molecular studies. As the individuals were congenitally blind initially known loci for LCA were excluded and later on known loci for retinal degeneration were searched. Linkage was found with micro satellite markers D6S1610, D6S1019 and D6S1017. Linkage studies revealed the presence of disease locus at 6p21.2.Two point lod score gave maximum value of 3.29 at θ=0, for micro satellite marker D6S1019.

Family-4 was designated as 8CBL diagnosed for autosomal recessive hereditary fundus dystrophy. The surname of the family was Rajput. In this kindred mostly consanguineous marriages were contracted, resulting in a higher number of affected children. Of the live members, 12 were affected including five males and seven females. Homozygosity mapping revealed the presence of disease locus at chromosome 22q12.1-q13.2. Which is a previously reported locus for dominant Sorsby’s fundus dystrophy. The micro satellite markers D22S280 and D22S685 showed hint of linkage with one branch through homozygosity mapping, while other 'two branches show homozygosity with different markers.

Family-5 was designated as 9CBL, diagnosed for autosomal recessive retinitis pigmentosa sine pigmento. The surname of the family was Arian. Mostly consanguineous marriages were contracted in the family resulted in a higher number of affected children. The kindred spans on five generations and consists of 45 individuals. Of which 27 were alive and eighteen were dead at the time of study. Of the live members, nine were affected including six males and three females. Nineteen family members were processed for molecular study. Of these 12 members were normal and seven were affected. Since in affected individuals night blindness was observed during first year of life, therefore, initially the affected members and their close degree relatives were screened to exclude the linkage to the regions of the previously described genes involved in LCA on chromosomes 1,6,14,17 and 19. During exclusion analysis, all the known loci for LCA were excluded. Then the known loci of autosomal recessive Retinitis Pigmentosa (RP), autosomal recessive and autosomal dominant Cone-Rod dystrophies and autosomal dominant Retinitis Pigmentosa (RP), were also excluded and linkage was observed at 8qll.q13 with micro satellite markers, D8S285 and D8S1113. Two-point linkage analysis resulted in a maximum lod score of3.11 for marker D8S285 at θ=0.

Present study revealed the presence of disease locus at LCA4 region (17p13.1) in 3CBL and 4CBL inbred pedigrees. We mapped the disease locus for autosomal recessive macular degeneration (7CBL) at 6p21.2 which is a previously reported locus for adMD and adRP from non-Asian populations (Dryja et al. 1997, Kajiwara et al. 1994).. In the present pedigree this disease region shows maximum lod score of 3.29 at θ=0, with marker D17S1019 for autosomal recessive inheritance. These results suggest that inheritance for macular degeneration could be genetically heterogeneous (Michaelides et al. 2003a). Similarly, in family 9CBL it shows linkage at 8qll-q13 but this locus has been reported for adRP (pierce et al. 1999; Jacobson et al.2000; Xu et al. 1996). In family 8CBL linkage may be shown in the disease region (22q13-qter2) due to homozygosity mapping because the family is highly inbred.

This study suggests that consanguineous marriages have a profound effect on the development of recessive eye disorders, and due to homozygosity autosomal recessive inheritance pattern is exhibited in all the families. A high percentage (60%) of consanguineous marriage has been observed in all the families studied here.

Download Full Thesis
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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
1270.38 KB
2 1 Leber’s Congenital Amaurosis 36
644.51 KB
  1.1 Introduction 38
  1.2 Results Family 3 Cbl 49
  1.3 Results Family 4cbl 56
  1.4 Discussion 56
3 2 Macular Degeneration 61
944.5 KB
  2.1 Introduction 61
  2.2 Results Family 7 Cbl 66
  2.3 Discussion 76
4 3 Fundus Dystrophy 84
379.75 KB
  3.1 Introduction 84
  3.2 Results Family 8 Cbl 85
  3.3 Discussion 94
5 4 Retinitis Pigmentosa 98
500.28 KB
  4.1 Introduction 98
  4.2 Results Family 9 Cbl 105
  4.3 Discussion 115
6 5 General Discussion 118
505.38 KB
  5.1 References 122