Barth syndrome: TAZ gene mutations, mRNAs, and evolution
Version of Record online: 25 MAR 2005
Copyright © 2005 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 134A, Issue 4, pages 409–414, 1 May 2005
How to Cite
Gonzalez, I. L. (2005), Barth syndrome: TAZ gene mutations, mRNAs, and evolution. Am. J. Med. Genet., 134A: 409–414. doi: 10.1002/ajmg.a.30661
- Issue online: 20 APR 2005
- Version of Record online: 25 MAR 2005
- Manuscript Accepted: 23 DEC 2004
- Manuscript Received: 22 JUN 2004
- Barth Syndrome Foundation (to Dr. Gonzalez)
- Barth syndrome;
- dilated cardiomyopathy;
- TAZ mRNA;
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, Δ5, Δ7, Δ5Δ7; (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: Δ5 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. © 2005 Wiley-Liss, Inc.