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Investigations of cataract genetics

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Burdon, Kathryn Penelope (2003) Investigations of cataract genetics. PhD thesis, University of Tasmania.

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Abstract

Familial cataract is a heterogeneous disorder, characterised by opacity of the lens
from an early age, often leading to blindness or severe visual disability.
Approximately 20% of congenital cataracts are inherited and can occur in isolation or
as part of over 200 genetic disorders. Many inherited cataracts also have an age of
onset during childhood and as such are not truly congenital, but have similar
aetiologies. There have been fourteen genes identified for isolated familial cataract,
but many of the molecular causes remain unknown. Forty-five pedigrees with various
forms of familial cataract have been collected from south-eastern Australia. This
collection includes 40 with autosomal inheritance, four with X-linked inheritance and
one with Nance-Horan Syndrome (NHS), an X-linked syndrome involving congenital
cataract, dental abnormalities and mental retardation. Linkage studies of the large pedigree with Nance-Horan Syndrome lead to the
refinement of the critical region for this disorder to 1.3 Mb through informative
recombination events. Coding regions of all six characterised genes in the region
were screened for mutations and shown not to be involved. A novel candidate gene
was identified in the draft human genome sequence using gene prediction programs,
EST information and comparison with other genomes available in public databases,
and the genomic structure of the gene was determined experimentally. The gene was
subsequently found to be expressed in all human tissues examined, including tissues
affected by NHS such as eye and brain. Additional NHS pedigrees were ascertained
and mutations of this novel gene were identified by direct sequencing in five of the
six NHS pedigrees. All mutations caused severe truncation of the predicted protein and were not identified in controls. Hence, this novel gene, although its function
remains unknown, is believed to be causative for Nance-Horan Syndrome.
Analysis of known cataract genes and loci by both linkage analysis and mutation
detection techniques in pedigrees with autosomal dominant congenital cataract
revealed three mutations in previously known cataract genes. These mutations
segregate with the cataract phenotype and are thought to be responsible for the
cataract observed in these pedigrees. In addition, linkage analysis in one large
pedigree has excluded linkage to most known loci, providing evidence for the
existence of an additional locus for isolated congenital cataract.
In summary, the molecular defect was determined in three large pedigrees with
isolated autosomal dominant congenital cataract, and a novel gene was identified and
shown to cause Nance-Horan Syndrome.

Item Type: Thesis (PhD)
Keywords: Cataract, Cataract
Copyright Holders: The Author
Copyright Information:

Copyright [Published Date as found in Millennium record] the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

Thesis (Ph.D.)--University of Tasmania, 2004. Includes bibliographical references

Date Deposited: 25 Nov 2014 00:53
Last Modified: 11 Mar 2016 05:54
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