English abstract
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high level of low density lipoprotein-cholesterol (LDL-C) in the blood leading to early coronary heart disease. An autosomal dominant variant of FH is caused by defects in LDL receptor (LDLR), proprotein convertase subtilisin kexin 9 (PCSK9) or apolipoprotein B (APOB) genes. However, an autosomal recessive variant caused by mutation in LDLR adaptor protein (LDLRAPI) gene.
The aims of this thesis are to identify index FH patients, detect mutation in FH associated genes and detect the effect of mutation on different structural levels of protein. As well as study their mode of inheritance.
In this study, a molecular analysis of LDLR, PCSK9 and APOB was performed in two Omani families. The two index patients were clinically diagnosed according to Simon Broome criteria. The 21 exons of LDLR gene, 12 exons of PCSK9 gene and exon 26 of APOB gene were analyzed by standard sequencing technique. Then, the pedigree of the two families were established. Moreover, the effect of detected mutations on different structural levels of protein was investigated using standard in silico modules.
In family 1, a frame sift mutation was detected in exon 3 of LDLR gene (c.272del) but no mutations were detected in PCSK9 and APOB genes. In family 2, a compound mutation was found in exon 4 of LDLR gene (c.G397A) and exon 9 of PCSK9 gene (c.A1420G).
In summary, I studied the mode of inheritance of two LDLR and one PCSK9 mutations in two Omani Arab families. Further, the effect of these mutations on the tertiary structure of the corresponding protein has been investigated with standard bioinformatics.
