Phenotypic Characterization of Female Carrier Mice Heterozygous for Tafazzin Deletion

SIMPLE SUMMARY: Barth syndrome (BTHS) is a disease that affects energy production. It results from mutations on the X chromosome, and thus it mainly affects males since they have only one copy (females have two X chromosomes). Although BTHS is rare, the consequences can be severe. BTHS affects the heart, immune system, and muscles, so boys and men with BTHS are at a high risk of heart attacks and death from infections, and they tire easily, which impacts quality of life. Women with one mutated X chromosome are typically thought to be asymptomatic, so they have not been studied very much. However, in other diseases caused by X chromosome mutations, females that were thought to be healthy developed symptoms after they got older. In this work, we studied female mice with one mutated X chromosome, which are models of female carriers of BTHS. We found that with advancing age, the carriers have some slowdown in their running speed, which is like that seen in male mice but less severe. They also weigh less and are better able to maintain their blood sugar, which could be beneficial. Our work shows that female carriers can have symptoms and supports further research in women. ABSTRACT: Barth syndrome (BTHS) is caused by mutations in tafazzin resulting in deficits in cardiolipin remodeling that alter major metabolic processes. The tafazzin gene is encoded on the X chromosome, and therefore BTHS primarily affects males. Female carriers are typically considered asymptomatic, but age-related changes have been reported in female carriers of other X-linked disorders. Therefore, we examined the phenotype of female mice heterozygous for deletion of the tafazzin gene (Taz-HET) at 3 and 12 months of age. Food intakes, body masses, lean tissue and adipose depot weights, daily activity levels, metabolic measures, and exercise capacity were assessed. Age-related changes in mice resulted in small but significant genotype-specific differences in Taz-HET mice compared with their female Wt littermates. By 12 months, Taz-HET mice weighed less than Wt controls and had smaller gonadal, retroperitoneal, and brown adipose depots and liver and brain masses, despite similar food consumption. Daily movement, respiratory exchange ratio, and total energy expenditure did not vary significantly between the age-matched genotypes. Taz-HET mice displayed improved glucose tolerance and insulin sensitivity at 12 months compared with their Wt littermates but had evidence of slightly reduced exercise capacity. Tafazzin mRNA levels were significantly reduced in the cardiac muscle of 12-month-old Taz-HET mice, which was associated with minor but significant alterations in the heart cardiolipin profile. This work is the first to report the characterization of a model of female carriers of heterozygous tafazzin deficiency and suggests that additional study, particularly with advancing age, is warranted.