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Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians

M Ogorelkova1, A Gruber, G Utermann

  • 1Institute of Medical Biology and Human Genetics, University of Innsbruck, Schoepfstrasse 41, 6020 Innsbruck, Austria.

Human Molecular Genetics
|September 15, 1999
PubMed

Insights

A common gene mutation in Caucasians causes a deficiency in lipoprotein(a) [Lp(a)], a particle linked to heart disease and stroke. This splice site mutation leads to a truncated apolipoprotein(a) [apo(a)] that cannot form the Lp(a) complex.

Area of Science:

  • Genetics
  • Cardiovascular Science
  • Molecular Biology

Background:

  • High plasma lipoprotein(a) [Lp(a)] concentrations are a risk factor for coronary heart disease and stroke.
  • Lipoprotein(a) levels are highly heritable, primarily determined by the apolipoprotein(a) [apo(a)] gene.
  • Congenital deficiency of Lp(a) suggests genetic causes influencing apo(a) function.

Purpose of the Study:

  • To investigate a specific genetic mutation in the apo(a) gene and its association with Lp(a) deficiency.
  • To elucidate the molecular mechanism by which the identified mutation affects Lp(a) complex formation and plasma levels.

Main Methods:

  • Genotyping for a G-->A splice site substitution in the apo(a) gene.
  • Reverse transcription-polymerase chain reaction (RT-PCR) to analyze apo(a) splicing.
  • Expression studies in HepG2 cells to assess apo(a) function and complex formation.
  • Immunoprecipitation of plasma apo(a) from affected individuals.

Main Results:

  • A G-->A substitution at the +1 donor splice site of the apo(a) Kringle IV type 8 intron is frequent in Caucasians (approx. 6%) but absent in Africans.
  • This mutation is strongly associated with congenital deficiency of plasma Lp(a) and accounts for a significant proportion of 'null' apo(a) alleles in Caucasians.
  • The mutation leads to alternative splicing, producing a truncated apo(a) that is secreted but fails to form the covalent Lp(a) complex, resulting in rapid degradation.

Conclusions:

  • A specific donor splice site mutation in the apo(a) gene is a common cause of Lp(a) deficiency in Caucasians.
  • The mutation disrupts Lp(a) complex formation due to an alternatively spliced, truncated apo(a) protein.
  • This molecular defect, followed by apo(a) degradation, explains the null Lp(a) phenotype associated with this common genetic variation.

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