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An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in

Zouhair Aherrahrou1, Lars C Doehring, Eva-Maria Ehlers

  • 1Department of Medicine II, Univerrsity of Luebeck, 23538 Luebeck, Germany. Zouhair.Aherrahrou@uk-sh.de

The Journal of Biological Chemistry
|January 19, 2008
PubMed

Insights

A specific mutation in the Abcc6 gene causes a splice variant, leading to protein deficiency and dystrophic cardiac calcification (DCC) in susceptible mice.

Area of Science:

  • Genetics and Molecular Biology
  • Cardiovascular Research
  • Biochemistry

Background:

  • Dystrophic cardiac calcification (DCC) is an autosomal recessive condition involving myocardial calcium phosphate deposits.
  • The Abcc6 gene is implicated in DCC, but the specific molecular variants causing the condition are not fully understood.

Purpose of the Study:

  • To identify the molecular variants in the Abcc6 gene responsible for dystrophic cardiac calcification (DCC) in mice.
  • To elucidate the mechanism by which Abcc6 variants lead to DCC at the molecular and protein level.

Main Methods:

  • Comparative sequencing of Abcc6 cDNA in DCC-resistant (C57BL/6) and DCC-susceptible (C3H/He) mice.
  • Analysis of splice variants and their impact on Abcc6 transcript and protein expression.
  • In vivo and in vitro studies using mouse tissues and transfected cells to assess protein deficiency.

Main Results:

  • A missense mutation (Cys619Thr) in Abcc6 was identified in DCC-susceptible mice, creating an alternative splice site.
  • This mutation leads to a 5-bp deletion in the Abcc6 transcript, resulting in premature protein termination and deficiency.
  • All tested mouse strains carrying the Thr allele and the resulting splice variant exhibited dystrophic cardiac calcification.

Conclusions:

  • A specific splice variant in the Abcc6 transcript, caused by a missense mutation, leads to MRP6 protein deficiency.
  • This Abcc6-related protein deficiency is a causative factor for dystrophic cardiac calcification in susceptible mouse strains.
  • The findings provide molecular insight into the genetic basis of DCC and the function of MRP6 protein.

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