Many of the obvious phenotypic differences between normal women and men are due to differential exposure to sex steroids. However, important disparities in cognitive, immunological and metabolic profiles, and the greater longevity of women are not explained by sex steroid effects. We think that differential X-chromosome-linked gene dosage contributes to important biological differences between females and males. Although it is commonly taught that dosage compensation for X-linked genes is achieved by X-inactivation in females, the finding of a distinct phenotype in 45,X females with Turner syndrome (TS) indicates that the second X chromosome is important for normal female development. We now realize that many X-chromosome genes may be asymmetrically expressed in normal women and men due to escape from X-inactivation and genomic imprinting, and may thus contribute to gender differences by dosage effects.
Our research aims to identify and define the function of X-chromosome genes involved in the differential development and function of brain, reproductive, metabolic and immune systems in women and men. ? The study of girls and women with TS provides a unique opportunity to elucidate X-chromosome gene dosage effects and to improve our understanding of this relatively common genetic disorder which affects approximately 1/2000 females. This research will improve our ability to care for patients with TS and enhance our understanding of disease processes such as the increased susceptibility to autoimmune disease in women and increased risk for coronary disease in men? The X-chromosome and longevity.? ? A major reason for the greater longevity of women is their relative protection, across all age groups, from ischemic heart disease. The more salutary metabolic profile enjoyed by women includes lower ?bad? LDL-cholesterol and higher ?good? HDL-cholesterol levels, and larger more buoyant lipid particles. This benign lipid profile is associated with a favorable distribution of adipose tissue in women. In contrast, normal men typically have higher LDL- and lower HDL-cholesterol and smaller, denser lipid particles, all independently associated with increased cardiovascular risk. This male lipid profile is associated with and probably causally related to the excess of intra-abdominal or visceral fat, typically found in men.? There are at least two mechanisms whereby a 2nd X chromosome could influence lipid metabolism. First, X-chromosome genes promoting a healthy lipid profile may escape inactivation and thus be active in two copies in 46.XX women. Alternatively, parental imprinting of X-linked genes involved in lipid metabolism may have favorable effects in women. For example, a gene that promotes healthy lipids could be imprinted, or silenced on the maternal X (Xmat) but active from the paternal X allele. Since men only receive a Xmat, they would be disadvantaged compared normal women who, because of random X inactivation, express the Xpat allele in about 50% of their cells. To test the hypothesis that X-chromosome genomic imprinting contributes to the metabolic differences between normal women and men, we compared metabolic profiles and regional fat distribution TS women that were monosomic for Xpat vs. those monosomic for Xmat. ? Women with a single maternally inherited X-chromosome had a significantly higher LDL-cholesterol, triglycerides and visceral fat compared with those with a pattern X. Interestingly, body mass index and total body fat were not different in the two groups, but fat concentrated within the abdomen was twice as great in the Xmat group. This male-type fat distribution and lipid profile in 45, Xmat women supports the view that differential X-chromosome gene dosage, determined by genomic imprinting, contributes to the excess mortality from ischemic heart disease in 46, XmatY men as well as 45, Xmat women. The identification of these genes clearly is of great clinical importance. ? ? Ovarian failure and psychosocial dysfunction.? To investigate the behavioral impact of early ovarian failure, we compared psychosocial functioning in women with TS and women with 46,XX premature ovarian failure. We reasoned that if the experience of premature ovarian failure per se leads to specific difficulties with social interactions in young women, then these two groups- despite their many differences - should demonstrate similar responses on tests of psychosocial function. Women with normal ovarian function served as contemporaneous controls for responses to a specific test battery focusing on social interaction. Our two ovarian failure groups reported virtually identical scores showing increased shyness and social anxiety and decreased self-esteem compared to women with normal ovarian function. These findings suggest that the shyness and poor self esteem seen in women with TS reflect the experience of premature ovarian failure. Current studies target the role of infertility, childlessness, sex steroid effects or altered body image in the impaired social functioning in young women with ovarian failure. ? ? Congenital cardiovascular defects in Turner syndrome ? Congenital cardiovascular disease may be the most serious medical consequence of X monosomy. Our MR study of 100 adults with TS revealed cardiovascular anomalies in ~50% of study subjects, in contrast to ~20% prevalence detected in echocardiographic studies. Whereas congenital heart defects in TS have been categorized as left-sided, outflow tract defects, MRA revealed a high prevalence of major venous malformations, including partial anomalous pulmonary venous return and persistent left superior vena cava affecting over 20% of the study population, making a major venous anomaly more prevalent than bicuspid aortic valve, previously regarded as the most common defect in TS. The most common anomaly defined in our study was a distinctive aortic deformation affecting ~50% of women with TS, termed elongated transverse arch. This newly described aortic abnormality may portend a risk for dissection, and hence we advise vigilant surveillance of aorta dimensions in affected patients. We also showed that the presence of neck webbing predicted underlying abnormal aortic valve and aorta structures, suggesting that fetal lymphedema is associated perhaps causally with the defects in cardiovascular development.? ? Our study has shown for the 1st time that individuals with TS have many cardiac electrophysiological abnormalities, including fascicular block, accelerated AV conduction, T wave abnormalities and prolongation of the rate-corrected QT interval (QTc). There was no relation between body habitus, cardiac dimensions, evidence of CHD, or metabolic parameters and the incidence of ECG abnormalities or QTc duration in TS. Thus, cardiac conduction and repolarization abnormalities appear to be intrinsic features of TS, suggesting that deletion of the second sex chromosome has more profound effects on the cardiovascular system than previously recognized, and that ECG analysis should be included in evaluating and monitoring patients with Turner syndrome. In particular, the QTc should be monitored if considering the use of medications known to prolong the QT and increase risk of cardiac arrhythmia, which include some antibiotics and psychotropics commonly used in children.
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| Bakalov, Vladimir K; Cheng, Clara; Zhou, Jian et al. (2009) X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab 94:3289-96 |
| Bondy, Carolyn A (2009) Turner syndrome 2008. Horm Res 71 Suppl 1:52-6 |
| McCarthy, Kateri; Bondy, Carolyn A (2008) Turner syndrome in childhood and adolescence. Expert Rev Endocrinol Metab 3:771-775 |
| Matura, Lea Ann; Ho, Vincent B; Rosing, Douglas R et al. (2007) Aortic dilatation and dissection in Turner syndrome. Circulation 116:1663-70 |
| Bondy, Carolyn A; Turner Syndrome Study Group (2007) Care of girls and women with Turner syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 92:10-25 |
| Matura, Lea Ann; Sachdev, Vandana; Bakalov, Vladimir K et al. (2007) Growth hormone treatment and left ventricular dimensions in Turner syndrome. J Pediatr 150:587-91 |
| Bondy, Carolyn A; Matura, Lea Ann; Wooten, Nicole et al. (2007) The physical phenotype of girls and women with Turner syndrome is not X-imprinted. Hum Genet 121:469-74 |
| King, Kelly A; Makishima, Tomoko; Zalewski, Christopher K et al. (2007) Analysis of auditory phenotype and karyotype in 200 females with Turner syndrome. Ear Hear 28:831-41 |
| Bondy, C A (2007) Heart disease in Turner syndrome. Minerva Endocrinol 32:245-61 |
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