TY - JOUR
T1 - Seven functional classes of barth syndrome mutation
AU - Whited, Kevin
AU - Baile, Matthew G.
AU - Currier, Pamela
AU - Claypool, Steven M.
N1 - Funding Information:
We would like to thank Dr Jeff Schatz and Carla Koehler (UCLA) for antibodies, and Drs Michael Schlame (NYU) and Wayne Riekhof (National Jewish) for help with the trans-acylase assays and isolating radiolabeled yeast phospholipids. This work was supported by National Institutes of Health (Grant number R00HL089185 to S.M.C.). M.G.B. is a predoctoral fellow of the American Heart Association.
PY - 2013/2
Y1 - 2013/2
N2 - Patients with Barth syndrome (BTHS), a rare X-linked disease, suffer from skeletal and cardiomyopathy and bouts of cyclic neutropenia. The causative gene encodes tafazzin, a transacylase, which is the major determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, CL. In addition to numerous frame shift and splice-site mutations, 36 missense mutations have been associated with BTHS. Previously, we established a BTHS-mutant panel in the yeast Saccharomyces cerevisiae that successfully models 18/21 conserved pathogenic missense mutations and defined the loss-of-function mechanism associated with a subset of the mutant tafazzins. Here, we report the biochemical and cell biological characterization of the rest of the yeast BTHS-mutant panel and in so doing identify three additional modes of tafazzin dysfunction. The largest group of mutant tafazzins is catalytically null, two mutants encode hypomorphic alleles, and another two mutants are temperature sensitive. Additionally, we have expanded the defects associated with previously characterized matrix-mislocalized-mutant tafazzins to include the rapid degradation of aggregation-prone polypeptides that correctly localize to the mitochondrial IMS. In sum, our in-depth characterization of the yeast BTHS-mutant panel has identified seven functional classes of BTHS mutation.
AB - Patients with Barth syndrome (BTHS), a rare X-linked disease, suffer from skeletal and cardiomyopathy and bouts of cyclic neutropenia. The causative gene encodes tafazzin, a transacylase, which is the major determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, CL. In addition to numerous frame shift and splice-site mutations, 36 missense mutations have been associated with BTHS. Previously, we established a BTHS-mutant panel in the yeast Saccharomyces cerevisiae that successfully models 18/21 conserved pathogenic missense mutations and defined the loss-of-function mechanism associated with a subset of the mutant tafazzins. Here, we report the biochemical and cell biological characterization of the rest of the yeast BTHS-mutant panel and in so doing identify three additional modes of tafazzin dysfunction. The largest group of mutant tafazzins is catalytically null, two mutants encode hypomorphic alleles, and another two mutants are temperature sensitive. Additionally, we have expanded the defects associated with previously characterized matrix-mislocalized-mutant tafazzins to include the rapid degradation of aggregation-prone polypeptides that correctly localize to the mitochondrial IMS. In sum, our in-depth characterization of the yeast BTHS-mutant panel has identified seven functional classes of BTHS mutation.
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U2 - 10.1093/hmg/dds447
DO - 10.1093/hmg/dds447
M3 - Article
C2 - 23100323
AN - SCOPUS:84872372503
VL - 22
SP - 483
EP - 492
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 3
M1 - dds447
ER -