title: Barth syndrome: TAZ gene mutations, mRNAs, and evolution.
abstract: Barth syndrome (MIM 302060) is an X-linked condition that includes dilated cardiomyopathy, neutropenia, failure to thrive, abnormal mitochondria, and 3-methylglutaconic aciduria. The mutated gene, TAZ, first described in 1996, appeared to produce a large set of alternatively spliced mRNAs with initiations of transcription upstream of exons 1 and 3. Since then, disease-causing mutations have been found in all exons including, most recently, a missense mutation in the controversial exon 5. Because of the initially described second initiation of transcription in intron 2, with in-frame initiation of translation in exon 3, we hypothesized that subjects with mutations in exons 1 and 2 would produce more normal "short product" that might attenuate their phenotype. Moreover, it was of interest to determine which splice variants were potentially functional as exon 5 is not present in yeast and rodents, and the variant lacking this exon is the most abundant. Using RT-PCR, we characterized TAZ mRNAs in cultured lymphocytes from nine subjects with Barth syndrome and two healthy controls. The TAZ genes and mRNAs of primates were also included. We found the following: (1) there is only one site for initiation of transcription, and the normal alternatively spliced assortment is limited to full-length, delta5, delta7, delta5delta7; (2) there are two alternative splice sites within introns 1 and 2 that could potentially produce an in-frame product; (3) exon 5 evolved into "exonhood" in the primate lineage after the split between Old World monkeys and hominoid primates; and (4) our results suggest that only two functional protein variants exist in lymphocytes: delta5 and full-length. Although exon 5 does not appear to be required for TAZ function in yeast and monkeys, its evolution to a highly conserved spliced exon in hominoid primates and the recent finding of an exon 5 mutation in a patient with Barth syndrome suggest that the full-length variant is important to TAZ function.
authors.affiliation: Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, USA. gonzalezil@comcast.net
authors.forename: Iris L
authors.initials: IL
authors.lastname: Gonzalez
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000217:Acyltransferases; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000473:pathology*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009503:Neutropenia / Q000473:pathology; D010802:Phylogeny; D011323:Primates / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA; D000217:Acyltransferases; C108675:TAFAZZIN protein, human