Gene dosage as a relevant mechanism contributing to the determination of ovarian function in Turner syndrome

Abstract

STUDY QUESTIONWhat is the burden of X chromosome mosaicism in the occurrence of spontaneous menarche (SM) in Turner syndrome (TS)?SUMMARY ANSWERSM was significantly associated with X chromosome mosaicism in the TS patients; a mosaicism with around 10% euploid cell line may predict spontaneous pubertal development when determined by molecular-cytogenetic techniques on uncultivated tissues.WHAT IS KNOWN ALREADYSpontaneous puberty can be observed in a minority of patients with TS, more frequently, but not exclusively, in those with a high level of 46,XX/45,X mosaicism at standard karyotype. The genetic mechanisms contributing to ovarian function in TS patients are still not determined. However, submicroscopic X-linked and autosomal copy number variations (CNVs) have recently emerged as an important genetic risk category for premature ovarian insufficiency and may be involved in modulating the TS ovarian phenotype.STUDY DESIGN, SIZE, DURATIONA group of 40 patients with a diagnosis of TS at conventional karyotyping participated in the study; 6 patients had SM and 34 patients had primary amenorrhoea (PA). All clinical data and the patients’ DNA samples were collected over the years at a single paediatric clinic.PARTICIPANTS/MATERIALS, SETTING, METHODSThe patients' samples were used to perform both genetic (Copy Number Assay) and molecular-cytogenetic (array-CGH and iFISH, interphase-FISH) analyses in order to evaluate the X chromosome mosaicism rate and to detect possible rare CNVs of genes with a known or predicted role in female fertility.MAIN RESULTS AND THE ROLE OF CHANCEAll TS patients showed variable percentages of the 46,XX lineage, but these percentages were higher in the SM group (P < 0.01). A mosaicism around 10% for the euploid cell line may predict spontaneous pubertal development when determined by molecular-cytogenetic techniques performed in uncultivated tissues. A few CNVs involving autosomal and X-linked ovary-related loci were identified by array-CGH analysis and confirmed by real-time quantitative PCR, including a BMP15 gene duplication at Xp11.22, a deletion interrupting the PAPPA gene at 9q33.1, and an intragenic duplication involving the PDE8A gene at 15q25.3.LIMITATIONS, REASONS FOR CAUTIONThis is a pilot study on a relatively small sample size and confirmation in larger TS cohorts may be required. The ovarian tissue could not be studied in any patients and in a subgroup of patients, the mosaicism was estimated in tissues of different embryonic origin.WIDER IMPLICATIONS OF THE FINDINGSThe combined determination of X chromosome mosaicism by molecular and molecular-cytogenetic techniques may become useful for the prediction of SM in TS. The detection of CNVs in both X-linked and autosomal ovary-related genes further suggests gene dosage as a relevant mechanism contributing to the ovarian phenotype of TS patients. These CNVs may pinpoint novel candidates relevant to female fertility and generate further insights into the mechanisms contributing to ovarian function.STUDY FUNDING/COMPETING INTEREST(S)...

Characterization of Spontaneous and Induced Puberty in Girls with Turner Syndrome

“…When evaluating the subgroup of girls with mosaic karyotypes, nearly 38% experienced spontaneous menarche. This is a higher proportion than that seen in a previously published assessment of 40 patients with mosaic TS, in which 15% had spontaneous menarche (15). Molecular-cytogenic analyses were performed to determine the degree of X chromosome mosaicism, and women with mosaicism of at least 10% were found to be significantly more likely to undergo spontaneous menarche than those with lower levels.…”

Genetics of primary ovarian insufficiency

“…The requirement for a double dosage of X-linked genes is supported by the complete spontaneous puberty reached in about one third of patients with high level mosaicisms (56,60). Recently, we documented the spontaneous puberty in one TS patient with short stature and a full duplication of the BMP15 gene on the short arm of X chromosome in presence of low level mosaicism (<10%), suggesting a relevant role for a double dose of this gene in ovarian development (60,61). X chromosome abnormalities have long been recognized as a frequent cause of many forms of familial as well as sporadic POI.…”

Chromosomal Abnormalities and Menstrual Cycle Disorders

“…One obvious explanation could also lie in the haploinsufficiency of loci on the X chromosome [12,14].…”

“…Castronovo et al performed a high-resolution comparative genome hybridization (CGH)-array analysis in a cohort of 45,X patients with or without spontaneous menarche [14]. They identified a tandem duplication of a single BMP15 gene in an 11-year-old patient with 45,X karyotype, who caught the pediatrician's attention because of a short stature but experienced a spontaneous menarche followed by regular menses for more than 4 years.…”

“…Consistent with haploinsufficiency of the short stature homeobox gene (SHOX), this patient was short (145 cm at 34 years) despite growth hormone treatment. BMP15 duplication on the conserved X chromosome might have preserved a sufficient gene dosage in the developing ovary during the first meiotic phases, when a double dose of X-linked genes is required [12,14]. BMP15 duplication led to the conservation of a certain amount of functional follicles at pubertal age and the ability to compensate, at least partially, for the loss of one copy of the other X-linked genes.…”