Collins, David-Roy; (1991) The role of the apolipoprotein B gene in the pathogenesis of familial hypocholesterolaemia. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The role of the apolipoprotein B (apoB) gene in the pathogenesis of two familial hypocholesterolaemic disorders, recessive abetalipoproteinaemia and familial hypobetalipoproteinaemia has been investigated. The structure of the apoB gene has been studied in four individuals with classical recessive abetalipoproteinaemia and four with familial hypobetalipoproteinaemia. In two individuals from one family with familial hypobetalipoproteinaemia, a point mutation was detected in one apoB allele which is predicted to lead to premature termination of apoB messenger RNA translation and thereby accounts for the hypocholesterolaemic phenotype. Since the mutation predicts the synthesis of an abnormal, truncated form of apoB, the apolipoproteins produced by one of these individuals were examined, but no such protein was detected. Similar experiments on two individuals from another family with hypobetalipoproteinaemia however, demonstrated the presence of a different, larger, truncated form of apoB. Subsequent studies revealed that this family had a frameshift mutation in one apoB allele which could fully account for the phenotype of one of the individuals, and partly account for phenotype of the other. The latter individual was found to have, in addition to the truncated apoB species, an abnormally low level of full length apoB. In an attempt to elucidate the molecular defect responsible for this finding, the 5' flanking region of the apoB gene was sequenced in this individual, but no abnormality was found. In contrast to the hypobetalipoproteinaemic individuals, no abnormalities in the apoB gene were detectable in any of the individuals with abetalipoproteinaeraia, The results of these studies however, did enable the transmission of the parental apoB alleles to the affected children to be followed. It is concluded that, within the families studied, the apoB gene is discordant with abetalipoprotei-naemia and that therefore, the disorder must be caused by a defect in another gene which is involved in the synthesis or secretion of apoB-containing lipoproteins from both the liver and intestine.

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