When silence is noise: Infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription

L. Ferri, C. Dionisi-Vici, R. Taurisano, F. M. Vaz, R. Guerrini, A. Morrone

Research output: Contribution to journalArticle

Abstract

Barth syndrome (BTHS) is an X-linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3-methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin (MLCL:L4-CL) ratio. We report a 6-year-old boy who presented with severe hypoglycemia, lactic acidosis and severe dilated cardiomyopathy soon after birth. The MLCL:L4-CL ratio confirmed BTHS (3.90 on patient's fibroblast, normal: 0-0.3). Subsequent sequencing of the TAZ gene revealed only the new synonymous variant NM_000116.3 (TAZ):c.348C>T p.(Gly116Gly), which did not appear to affect the protein sequence. In silico prediction analysis suggested the new c.348C>T nucleotide change could alter the TAZ mRNA splicing processing. We analyzed TAZ mRNAs in the patient's fibroblasts and found an abnormal skipping of 24 bases (NM_000116.3:c.346_371), with the consequent ablation of 8 amino acid residues in the tafazzin protein (NP_000107.1:p.Lys117_Gly124del). Molecular analysis of at risk female family members identified the patient's sister and mother as heterozygous carriers. Apparently harmless synonymous variants in the TAZ gene can damage gene expression. Such findings widen our knowledge of molecular heterogeneity in BTHS.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

Barth Syndrome
Noise
Fibroblasts
Genes
Inborn Errors Metabolism
Lactic Acidosis
Messenger RNA
Muscle Hypotonia
Cardiolipins
Gene Dosage
Dilated Cardiomyopathy
Muscular Diseases
Neutropenia
Cardiomyopathies
Hypoglycemia
Computer Simulation
Siblings
Proteins
Nucleotides
Mothers

Keywords

  • Barth syndrome
  • Exon skipping
  • Silent mutation
  • Synonymous mutation
  • TAZ gene

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

When silence is noise : Infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription. / Ferri, L.; Dionisi-Vici, C.; Taurisano, R.; Vaz, F. M.; Guerrini, R.; Morrone, A.

In: Clinical Genetics, 2016.

Research output: Contribution to journalArticle

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