ABSTRACT
INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused
by mutations in the CFTR gene. The gene mutation profile is extremely
heterogeneous and mutations show a variable distribution among population
groups. In SA the 3120+1G->A splice site mutation has been found
predominantly in Black and Coloured patients. It occurs in Black CF patients at
an estimated frequency of 46%. The CF carrier frequency is estimated at 1/34 in
Black and 1/55 in Coloured populations, and based on these rates, it is clear that a
significant number of Black and Coloured patients remain undiagnosed.
Point mutations account for the majority of the mutations that have been found in
the CFTR gene. Copy number mutations are, however, increasingly being
detected in CF patients through the use of gene dosage-dependant assays. These
mutations have been found to occur in the CFTR gene in various African
American families and exon rearrangements are thought to account for 1.3% of all
CF chromosomes across all populations. AIMS: To use haplotypes to analyse the
origin(s) of the 3120+1G->A mutation and the likely frequencies of the remaining
unknown mutations. To increase mutation detection in the SA Black and
Coloured groups by searching for CFTR gene exons for copy number mutations.
METHODS: In patients with at least one copy of the 3120+1G>A mutation
haplotype studies will be used to elucidate the origin(s) of this mutation in SA
Black and Coloured CF patients, by analyzing pyrosequencing SNP genotype
data. In patients with at least one unknown mutation, haplotype studies will
reveal the likely relative frequencies of the unknown mutations in these
populations. In Black and Coloured CF patients with at least one unknown
mutation, a multiplex ligation dependant probe amplification (MLPA) CF kit will
be used for the detection of exon copy number mutations. RESULTS: The
results of the haplotype data show that there is a G-G-C-G-T-A haplotype, for
markers MetD-KM19-J44-T854T-Tub18-J32, associated with the 3120+1G->A
mutation in both Black and Coloured patients. Unknown mutation-associated
haplotypes indicate that there are two relatively common unknown mutations in
each of these populations. MLPA results show that one patient is a carrier of an exon 2 deletion. CONCLUSION: A single origin for the 3120+1G>A mutation
in Black and Coloured CF patients is supported by the data. Exon copy number
changes in the CFTR gene are not a major mutational mechanism leading to CF in
SA Black and Coloured patients.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/5689 |
| Date | 23 September 2008 |
| Creators | De Carvalho, Candice Lee |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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