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Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome

Tzipora C Falik-Zaccai1,2, Yiftah Barsheshet2, Hanna Mandel3,4

  • 1Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel falikmd.genetics@gmail.com orly.avni@biu.ac.il.

EMBO Molecular Medicine
|January 11, 2017
PubMed

Insights

A novel genetic disorder, dilated cardiomyopathy (DCM) with cardio-cutaneous syndrome, was identified in infants due to a PPP1R13L gene mutation. This mutation impairs iASPP protein function, leading to fatal cardiac inflammation.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Dilated cardiomyopathy (DCM) is a severe heart condition with a largely unknown genetic cause.
  • Infants presented with DCM, skin, teeth, and hair abnormalities, succumbing before age three.

Purpose of the Study:

  • To identify the genetic basis of a novel cardio-cutaneous syndrome presenting with DCM in infants.
  • To investigate the role of the iASPP protein in cardiac inflammation and DCM pathogenesis.

Main Methods:

  • Genetic sequencing identified homozygous variations in PPP1R13L in affected infants.
  • Fibroblast and cardiomyocyte cell models, along with mouse models, were used to study gene function.
  • RNA sequencing and NF-κB pathway analysis were performed to understand molecular mechanisms.

Main Results:

  • A homozygous PPP1R13L mutation causing a premature stop codon was found in affected infants.
  • iASPP deficiency led to increased pro-inflammatory cytokine gene expression and heightened sensitivity to lipopolysaccharide (LPS).
  • NF-κB pathway activation was identified as a key mechanism in the observed cardiac inflammation.

Conclusions:

  • PPP1R13L is identified as the gene responsible for a new autosomal-recessive cardio-cutaneous syndrome.
  • iASPP plays a critical role in regulating cardiac inflammatory responses to common stressors.
  • Failure to regulate these pathways contributes to fatal infantile DCM.

Keywords:
PPP1R13Ldilated cardiomyopathygeneticsinflammationmyocarditis

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