For many years the second X chromosome in females was viewed as totally inert, due to the process of random X-inactivation. Since it seemed that each sex had only one functional X chromosome, it was assumed that the only genetic difference between sexes derived from Y chromosome-encoded testis-determining genes. Thus, phenotypic differences between the sexes were attributed to differential exposure to gonadal steroids, i.e., estrogen in females and androgen in males. While many sex differences are clearly due to sex steroids, some important distinctions such as the greater longevity of women, are not adequately explained by sex steroid effects. Moreover, it is difficult to reconcile the view that only one X chromosome was actually functional in normal females with the fact that there is a distinct phenotype in girls with monosomy for the X chromosome, or Turner syndrome (TS). Indeed, the study of TS shows that the 2nd X chromosome is essential for normal female development. X-chromosome and congenital cardiovascular disease: We now know that 15-20% of genes on the 2nd X chromosome escape X-inactivation. Pseudoautosomal X-chromosome genes have Y chromosome homologues and behave like autosomal genes with expression from both X chromosomes in females and from X- and Y-chromosomes in males. For example, haplo-insufficiency for a pseudoautosomal gene known as SHOX causes short stature and skeletal defects in TS. We hypothesize that the congenital cardiovascular defects (CHD) found in about 50% of patients with TS are due to haploinsufficiency for an as yet unknown pseudoautosomal gene. Supporting this view, we have mapped the critical region for CHD in TS patients to the distal short arm (Xp;Matura et al., 2007;Sachdev et al., 2008), which contains the major pseudoautosomal region. Moreover, the murine X chromosome has lost the Xp pseudoautosomal region, and the mouse has a minimal XO phenotype;in contrast, the cat and dog, which have high Xp pseudoautosomal homology to the human, have an XO phenotype similar to human patients, including CHD. Thus we are focusing on candidate Xp pseudoautosomal genes that are conserved in canine, feline and human. TS is the leading cause of fatal aortic dissection in young women. It is unclear whether all women with TS areat risk, or if only those with known CHD are at risk of acute aortic dissection. Moreover, it was unknown if aortic root dilation precedes and predicts aortic degeneration as in Marfan syndrome. We recently reported the first prospective measure of the incidence of aortic dissection in TS and proposed new guidelines to identify high risk patients (Matura et al., 2007). We showed that aortic dilation at the level of the ascending aorta was indeed predictive of aortic dissection, but dilation was only recognized after normalization for the small body size of TS women. Current studies are investigating the role of the TGF-beta system in the Turner aortopathy by measuring TGF-beta components in our patients in relation to aortic dimensions and dynamic changes. We also aim to determine whether treatment to suppress TGF system activity can arrest or reverse aortic dilation in individuals with TS. X-chromosome, genomic imprinting and longevity: Genomic imprinting of X-chromosome gene expression may also to male-female differences and to the TS phenotype. Genomic imprinting involves the selective expression of certain genes determined by their parental origin;imprinting of X-linked genes causes different gene expression in males and females, since normal women are mosaic for maternally and paternally inherited active X chromosomes (XM and XP), while men are monosomic for XM. Genes imprinted (silenced) on XM would still be expressed in females from 50% of cells, but not expressed in males. Women enjoy greater longevity than men mainly due to their lower risk, across all age groups, for ischemic heart disease. The key advantage women have in this regard is their salutary, gynoid fat distribution, meaning adipose tissue preferentially concentrated subcutaneously in the hips and thighs. In contrast, men tend to concentrate fat in the abdominal area, especially intraperitoneal visceral fat, which has many adverse metabolic effects, including an atherogenic lipid profile and a chronic inflammatory state associated with high cardiovascular risk. Estrogens seem to promote the peripheral disposition of apparently healthy fat in maturing females, but testosterone is not responsible for the selective accumulation of abdominal fat in males. Based on observations on the body habitus of women with TS and a sole XM, we hypothesized that parental imprinting of X-linked genes involved in regional fat distribution and lipid metabolism may promote android, or central fat accumulation. To test the hypothesis we compared regional fat distribution and lipid profiles in groups of women that were monosomic for XM vs. XP. The XM and XP groups had similar BMI and total body fat, but women with a single maternally inherited X-chromosome had 2-fold greater abdominal and specifically intra-abdominal, or visceral fat compared to those with XP. This was associated with a distinctly atherogenic lipid profile compared to the paternal X group. The male-type fat distribution and lipid profile in XM women supports the view that differential X-chromosome gene dosage, determined by genomic imprinting, contributes to abdominal adiposity and excess ischemic heart disease in 46,XY men. Because of the different parental origins of the X chromosome in males and females, in contrast to autosomal imprinting, X genomic imprinting should be associated with differential effects depending on the sex of the offspring as well as the parent of origin. Thus, we predicted that X-linked imprinting does not regulate traits that are not sexually dimorphic such as renal or cardiac development. We proved this by showing equal prevalence of renal and cardiovascular defects in XM vs. XP groups with TS. Somatic size, however, is sexually dimorphic (men >> women), and we have provided evidence that this is related to maternal X chromosome (Bondy et al, 2007). In addition to heart disease, an increased risk of diabetes mellitus has been noted in TS, but the specific phenotype and genetic etiology of this trait are unknown. Thus,we examined the prevalence of DM and of impaired glucose tolerance (IGT) using an oral glucose tolerance test (OGTT) in adults with TS. Insulin sensitivity and secretion were compared in groups of age- and BMI-matched euglycemic women with TS and healthy female controls by OGTT. We compared gene expression profiles in lymphocytes from differentially affected TS groups using DNA arrays. Type 2 DM was present in 56/224 (25%) of women with TS while classic type 1 DM was found in only one (0.45%). DM was significantly more prevalent among women with an isoXq chromosome compared to X monosomy (4O vs. 18.8%, p=0.004). Euglycemic women with TS (n=72;age 3312;BMI 233) had significantly higher glycemic and lower insulin secretory responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in a number of potentially diabetogenic autosomal transcripts in the isoXq group. We conclude that type-2 DM due to primary beta-cell defect is significantly increased among women with monosomy for the X chromosome, but is even more greatly increased among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.

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Prakash, Siddharth; Guo, Dongchuan; Maslen, Cheryl L et al. (2014) Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome. Genet Med 16:53-9
Gutin, Liat S; Merz, Alexa E; Bakalov, Vladimir K et al. (2013) Parity and aortic dimensions in healthy women. Int J Cardiol 165:383-4
Bondy, Carolyn; Bakalov, Vladimir K; Cheng, Clara et al. (2013) Bicuspid aortic valve and aortic coarctation are linked to deletion of the X chromosome short arm in Turner syndrome. J Med Genet :
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Gould, Harley N; Bakalov, Vladimir K; Tankersley, Carolyn et al. (2013) High levels of education and employment among women with Turner syndrome. J Womens Health (Larchmt) 22:230-5
Oza, Nishaki Mehta; Siegenthaler, Michael; Horvath, Keith et al. (2013) Serious aortic complications in a patient with Turner syndrome. Eur J Pediatr 172:703-5
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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
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Wooten, Nicole; Bakalov, Vladimir K; Hill, Suvimol et al. (2008) Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab 93:2109-14

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