Spinocerebellar ataxia with retinal degeneration: from phenotype to gene to protein.

Update item information
Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Gouw, Launce G.
Title Spinocerebellar ataxia with retinal degeneration: from phenotype to gene to protein.
Date 2001-12
Description This dissertation describes a hereditary neurological disorder, autosomal dominant cerebellar ataxia with retinal degeneration, from initial clinical findings through analysis and isolation of the responsible gene, to study of the affected protein. The work described herein follows a research arc beginning with a patient presenting with worsening coordination and progressive blindness. A detailed clinicopathologic description of the signs, symptoms and autopsy findings occurring in affected related individuals ensued, creating strict criteria for the disease and establishing it as a distinct genetic entity. Subsequent linkage analysis allowed me to localize the gene responsible for the disease to chromosome 3p14-21.1. I named the disease spinocerebellar ataxia type 7 and the gene SCA7. I undertook experiments to isolate SCA7, which was eventually cloned. As I had hypothesized, SCA7 harbored a dynamic mutation due to an unstable region of DNA within the gene. This region, a trinucleotide repeat, is relatively short and stable in the general population, but expanded and unstable in affected individuals. I observed a direct correlation between repeat length and disease severity, and an inverse correlation with age-of-onset. I found allele instability and rate of disease transmission depended upon the sex of the parent transmitting the allele. The dissertation concludes with specific observations of SCA7's protein, ataxin-7. The SCA7 trinucleotide repeat generates a tract of glutamine amino acids within ataxin-7; I noted ataxin-7 had a nuclear distribution, forming subnuclear aggregates with a morphology that depended, in part, on glutamine tract length. My data infers ataxin-7s role in apoptosis, or programmed cell death. I demonstrated that ataxin-7 is specifically cleaved by caspase-7, an executioner of apoptosis. Furthermore, I noted longer glutamine tracts within ataxin-7 correlated with increased proapoptotic effects in cells expressing the protein. I modified ataxin-7 to confer caspase-7 cleavage resistance to prepare for further investigation into the protein's apoptotic role. The findings in this dissertation offer insights into the function and pathology of SCA7, the gene responsible for spinocerebellar ataxia with retinal degeneration. It is hoped that the information described in this manuscript may eventually lead to therapeutic modalities for what is currently an inexorable, often fatal disease.
Type Text
Publisher University of Utah
Subject DNA; Neuropathology
Subject MESH Ataxia; Genetics; Retinal Degeneration
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Spinocerebellar ataxia with retinal degeneration : from phenotype to gene to protein." Spencer S. Eccles Health Sciences Library. Print version of "Spinocerebellar ataxia with retinal degeneration : from phenotype to gene to protein." available at J. Willard Marriott Library Special Collection. RC39.5 2001 .G68.
Rights Management © Launce G. Gouw.
Format Medium application/pdf
Identifier us-etd2,216
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
ARK ark:/87278/s60p1dmt
Setname ir_etd
Date Created 2012-04-23
Date Modified 2021-05-06
ID 193121
Reference URL https://collections.lib.utah.edu/ark:/87278/s60p1dmt
Back to Search Results