Mutation Characterization and Genotype-Phenotype Correlation in Barth Syndrome

Abstract

Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-methylglutaconic aciduria. Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome. We have now evaluated 14 Barth syndrome pedigrees for mutations in G4.5 and have identified unique mutations in all, including four splice-site mutations, three deletions, one insertion, five missense mutations, and one nonsense mutation. Nine of the 14 mutations are predicted to significantly disrupt the protein products of G4.5. The occurrence of missense mutations in exons 3 and 8 suggests that these exons encode essential portions of the G4. 5 proteins, whose functions remain unknown. We found no correlation between the location or type of mutation and any of the clinical or laboratory abnormalities of Barth syndrome, which suggests that additional factors modify the expression of the Barth phenotype. The characterization of mutations of the G4.5 gene will be useful for carrier detection, genetic counseling, and the identification of patients with Barth syndrome who do not manifest all of the cardinal features of this disorder.

Novel missense mutation (R94S) in the TAZ (G4.5) gene in a Japanese patient with Barth syndrome

“…PCR products digested with SfaNI showed that the patient was hemizygous for the R94S mutation. The mother of the patient was heterozygous same position (R94C) has been previously reported (Johnston et al 1997). These data suggest that R94S is not a common polymorphism, but a disease-causing mutation.…”

Infantile Dilated X-Linked Cardiomyopathy, G4.5 Mutations, Altered Lipids, and Ultrastructural Malformations of Mitochondria in Heart, Liver, and Skeletal Muscle

“…Respiratory chain abnormalities, reported in other patients with X-linked DCM (Barth et al, 1983(Barth et al, , 1996, were not found in our patients. Relating genotype to phenotype has been difficult previously (Cantlay et al, 1999;D'Adamo et al, 1997;Johnston et al, 1997) and remains difficult today.…”

“…lished missense mutations, 7 occur in these motifs. Mutations V183G and G197E have been found repeatedly (Bleyl et al, 1997;Cantlay et al, 1999;D'Adamo et al, 1997;Ichida et al, 2001;Johnston et al, 1997;Neuwald, 1997). The significant clustering of over one-half the reported disease-causing mutations in putative acyltransferase motifs (p Ͻ 0.022, 2 test) may reveal regions of the tafazzin protein critical for its function.…”

“…D'Adamo et al (1997) analyzed G4.5 in 11 families with X-linked DCM and suggested that the type of mutation influenced the disease phenotype. Johnston et al (1997) analyzed 19 different X-linked DCM pedigrees and found no relationship between type or location of G4.5 mutation and severity of heart disease, neutropenia, or 3-methylglutaconic aciduria. Neuwald (1997) pointed out that tafazzins have acyltransferase homology and suggested that they may be involved in maintaining mitochondrial morphology and function.…”

The in-depth evaluation of suspected mitochondrial disease

“…Complex I structural subunits [151], B17.2L & NDUFAF1 [151], SDHA [152], SDHC [153], SDHD [153], BCS1L [154,155], SURF1 [156], SCO1 [157], SCO2 [158], COX10 [159], COX15 [160,161], ETHE1 [162], LRPPRC (LSFC) [138], ATP12 [163], PDSS1 [164], PDSS2 [165], COQ2 [164], APTX [166], ADCK3 [167], ETFDH [168], TSFM [169], TUFM [170], EGF1 [170], MRPS16 [171], PUS1 [172], DARS2 [173], PDHA1 [14], POLG1 [107], TK2 [174,175], DGUOK [176], MPV17 [137], SUCLA2 [177],SUCLG1 [177],RRM2B [178], TWINKLE [179], ANT1 [180], ABC7 [181], FXN [182], OPA1 [183], DDP1 [184], SPG7 [185,186], TAZ [187] …”