The Hypothesis of the Prolonged Cell Cycle in Turner Syndrome

Abstract

Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally abnormal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.

Cell Cycle Kinetics and Sister Chromatid Exchange in Mosaic Turner Syndrome

“…It has been suggested that 45,X lineages have a prolonged cell cycle that can affect the differentiation of tissues and organs [7]. These preliminary data indicate that there could be an association between a prolonged cell cycle and the phenotypic features in TS [3].…”

“…PI of 46,XN lineage was slightly higher than the 45,X lineage, suggesting 45,X lineages had a proliferative disadvantage in relation to 46XN lineages. A previous study with skin fibroblast cultures comparing differences in cell cycle of aneuploid cell lines (45,X) to cell lines with structural anomalies of the X chromosome, and normal diploid cell lines, 46,XX and 46,XY, showed the cell cycle of 45,X cell lines was significantly longer compared to euploid controls [3]. A possible explanation for this phenomenon would be a longer S phase, resulting in a prolonged inter-mitotic period in 45,X cells that could lead to a decrease in their quantity during organogenesis, which could contribute to important phenotypical features in TS [3,7].…”

“…Monosomies are relatively common events in early embryonic development, but survival beyond fetal period is exceptional [3]. The embryonic and fetal survival of 45,X concepts although extremely low (0.01%) can result in live births, which can be explained by the fact that it is a monosomy of sex chromosomes.…”

“…It is a hallmark in tumorigenesis and is also common during early human embryogenesis [11]. CIN can be associated with monosomy-trisomy of a whole chromosome and other genomic and chromosomal variations [3].…”