Mailly, France; (1995) Mutations in the human lipoprotein lipase gene and their relationship to hyperlipidaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The enzyme lipoprotein lipase (LPL) is a key participant in the catabolism of triglyceride-rich plasma lipoproteins. The absence of LPL activity leads to type I hyperlipoproteinaemia and it has been suggested that partial deficiency may be involved in the development of combined hyperlipidaemia. This thesis describes the detection and identification of mutations in the human lipoprotein lipase (LPL) gene and investigates their potential biological significance and impact on plasma lipid levels. Single-stranded conformation polymorphism (SSCP), in combination with sequencing, was used to screen a group of twenty individuals with type I hyperlipoproteinaemia for mutations in exons 2 to 9 of the LPL gene. Thirteen separate mutations were identified, six were in exon 5 and four in exon 6. Twelve of these were single nucleotide substitutions, of which ten resulted in an amino acid change and there was one small deletion, leading to premature termination. Eight of these mutations were novel to this study. The previously reported G188E substitution was the only mutation present in more than one proband. The A158T and S193R substitution were shown by in vitro mutagenesis and expression in mammalian cells to completely abolish enzyme activity, while the N291S decreased it by 50%. The approach described above was also applied to screen a subset of 35 hyperlipidaemic individuals with combined hyperlipidaemia and/or low lipase activity. One SSCP variant was identified in exon 2 in three individuals resulting in the substitution of Asn for Asp at amino acid 9. Both in vivo and in vitro studies showed that D9N decreased both LPL activity and mass. A DNA pooling strategy was developed which allowed rapid screening of over 2200 individuals from six studies for this substitution (1000 patients/hyperlipidaemics and 1200 controls). The carrier frequency of the Asn9 variant was almost twice as high in the patient group compared to controls and the study of a subset of carriers with regards to plasma lipid levels suggested that the Asn9 variant was associated with lower LPL activity and a tendency to elevated triglycerides. The commonest LPL mutation found in type I subjects (G188E) was rare (< 1%) or absent in the various study subsets. In contrast, the N291S substitution was relatively common (2.8% in the general population control sample) and had a weak impact on triglyceride levels. Thus, biologically important variants of the LPL gene are present in the general population and are likely to contribute to the risk of developing hyperlipidaemia and heart disease.

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