| dc.contributor.author | Morash, Barbara A. | en_US |
| dc.date.accessioned | 2014-10-21T12:37:58Z | |
| dc.date.available | 1996 | |
| dc.date.issued | 1996 | en_US |
| dc.identifier.other | AAINN15938 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/55140 | |
| dc.description | Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the LDL receptor gene (Brown and Goldstein, 1986). Heterozygous FH is a common genetic disorder with an estimated frequency of 0.2% among the general population. Clinically, patients present with elevated plasma LDL-cholesterol levels, tendinous xanthomas, premature atherosclerosis and myocardial infarction within the fourth or fifth decade of life. Currently, diagnosis of FH relies on clinical phenotype. However, clinical criteria do not always permit unequivocable diagnosis of heterozygous FH and, therefore, molecular diagnostic techniques are extremely valuable in this regard (Kotze et al., 1992; Lestavel-Delattre et al., 1994; Schuster et al., 1995). | en_US |
| dc.description | This thesis identifies a novel mutation, a cytosine to guanine substitution, at the third position of codon 152 in exon 4 of the LDL receptor gene in a Nova Scotian family clinically diagnosed with heterozygous FH. The mutation was identified by direct dideoxy sequence analysis of the LDL receptor gene and confirmed by cDNA sequencing. The mutation at codon 152 results in a cysteine $\to$ tryptophan substitution in the ligand binding domain of the LDL receptor protein which is expected to distort and destabilize protein structure in this critical region. Functional assays suggested decreased ligand binding as the cause of FH in this family, a finding consistent with a mutation of this nature in exon 4. | en_US |
| dc.description | The mutation at codon 152 creates a recognition sequence for the restriction endonuclease BsrI. Based on this finding, a diagnostic approach was developed to screen for the mutation using BsrI restriction analysis of a 160bp amplicon spanning the mutation. This analysis showed that the mutation segregated with the disease in this family and is the probable cause of FH in this kindred. The C $\to$ G substitution at the third position of codon 152 was not found in 11 other putatively unrelated families clinically diagnosed with heterozygous FH. Screening additional families over the next few years will determine the precise frequency of this mutation in the Maritime Provinces. BsrI analysis for the detection of the C $\to$ G substitution at codon 152 is currently being used at the Queen Elizabeth II Health Sciences Centre for the diagnosis of heterozygous FH. | en_US |
| dc.description | In addition, an individual with familial defective apoB-100 (FDB) was identified, by molecular analysis, in a group of 13 patients clinically diagnosed with heterozygous FH. This finding demonstrates the need for molecular analysis to distinguish between FDB and FH and has been instrumental in establishing a routine screening program for the detection of FDB among heterozygous FH patients at the Queen Elizabeth II Health Sciences Centre. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 1996. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Biology, Molecular. | en_US |
| dc.subject | Biology, Genetics. | en_US |
| dc.subject | Health Sciences, Pathology. | en_US |
| dc.title | A novel mutation at codon 152 in exon 4 of the LDL receptor gene which results in decreased ligand binding and familial hypercholesterolemia in a Nova Scotian kindred. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
