Molecular Genetics of Hypobetalipoproteinaemia and Abetalipoproteinaemia

Abstract

Genetic disorders of lipoprotein metabolism can cause marked hypocholesterolaemia with low or absent low‐density lipoprotein (LDL) cholesterol and apolipoprotein B (apoB) concentrations in plasma, depending on the gene involved and mode of inheritance of the condition, together with the severity of the mutation or mutations present. Hypobetalipoproteinaemia is defined as a plasma LDL cholesterol and apoB less than the 5th centile for age and sex, and when mutations in the APOB gene are inherited in a codominant fashion is known as familial hypobetalipoproteinaemia (FHBL). Abetalipoproteinaemia, which is clinically indistinguishable from homozygous FHBL, is a very rare recessive disorder caused by mutations in MTTP and characterised by the absence of apoB‐containing lipoproteins in the plasma. Loss‐of‐function mutations in PCSK9 , particularly nonsense mutations, are also associated with hypobetalipoproteinaemia, but lack any clinical features. More recently, mutations in ANGPTL3 were found to cause recessive familial combined hypolipidaemia, characterised by a reduction in all plasma lipids. Key Concepts: Hypobetalipoproteinaemia is defined as low levels (<5th centile) of plasma LDL cholesterol and apolipoprotein B, whereas in abetalipoproteinaemia these analytes may be undetectable. Heterozygous FHBL is generally caused by truncations in apoB, and is associated with hepatic steatosis and a low risk of cardiovascular disease. Homozygous FHBL and abetalipoproteinaemia result in a variable clinical phenotype and are caused by mutations in APOB and MTTP , respectively. Loss‐of‐function mutations in PCSK9 are associated with low plasma LDL cholesterol concentrations and low risk of cardiovascular disease, and no clinical phenotype. ANGPTL3 mutations cause familial combined hypolipidaemia, a newly described recessive condition characterised by reductions in all plasma lipids.

Novel missense MTTP gene mutations causing abetalipoproteinemia

“…ABL is caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene [1][2][3] and affected individuals often present in childhood with failure to thrive, fat malabsorption, acanthocytosis, and vitamin E deficiency [4,5]. Patients with ABL cannot be distinguished clinically from compound heterozygous and homozygous familial hypobetalipoproteinemia (OMIM 101130), which is caused by mutations in the APOB gene [5][6][7].…”