title: When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription.
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.
authors: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.|Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, Florence, Italy.
authors: L
authors: L
authors: Ferri
authors: Department of Pediatric Medicine, Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children's Research Hospital, Rome, Italy.
authors: C
authors: C
authors: Dionisi-Vici
authors: Department of Pediatric Medicine, Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children's Research Hospital, Rome, Italy.
authors: R
authors: R
authors: Taurisano
authors: Department of Clinical Chemistry and Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors: F M
authors: FM
authors: Vaz
authors: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.|Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, Florence, Italy.
authors: R
authors: R
authors: Guerrini
authors: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy. a.morrone@meyer.it.|Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, Florence, Italy. a.morrone@meyer.it.
authors: A
authors: A
authors: Morrone
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics / Q000503:physiopathology; D000217:Acyltransferases; D056889:Barth Syndrome / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D002308:Cardiolipins / Q000097:blood; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000503:physiopathology; D008246:Lysophospholipids / Q000097:blood; D008297:Male; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002308:Cardiolipins; D008246:Lysophospholipids; D014157:Transcription Factors; C067188:monolysocardiolipin; C523441:tetralinoleoylcardiolipin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Barth syndrome; TAZ gene; exon skipping; silent mutation; synonymous mutation