STAG3 truncating variant as the cause of primary ovarian insufficiency

Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI

The urethra during pelvic floor contraction: Observations on three-dimensional ultrasound

OBJECTIVE: To investigate with three-dimensional ultrasound how voluntary pelvic floor contractions influence the morphology of the female urethra's components

Umbilical cord leptin predicts neonatal bone mass

Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences on bone development during intrauterine and early postnatal life. A potential role for fetal leptin in mediating these effects is suggested by animal studies showing that leptin influences prenatal osteoblast growth and development, and that fetal leptin concentrations are altered by changes in maternal nutrition. In a group of term human infants we reported previously that maternal birthweight, smoking, fat mass, and exercise during late pregnancy independently predict neonatal bone mass. To investigate the potential role of leptin in mediating these effects, we now relate leptin concentrations in umbilical venous serum to neonatal bone mass and body composition in 117 infants. There were strong positive associations between umbilical venous leptin concentration and each of whole body bone mineral contents (BMC) (r = 0.42, P ? 0.001) and estimated volumetric bone density (r = 0.21, P = 0.02); whole body lean mass (r = 0.21, P ? 0.024); and whole body fat mass (r = 0.60, P < 0.001). The associations with neonatal BMC and fat mass, but not with lean mass, were independent of associations that we have reported previously between cord serum insulin-like growth factor 1 (IGF-1) concentrations and neonatal body composition. Among the maternal determinants of neonatal bone mass, cord leptin explained the relationship with maternal fat stores, but not those with the mother’s own birthweight, smoking, or physical activity. We conclude that umbilical venous leptin predicts both the size of the neonatal skeleton and its estimated volumetric mineral density. In addition, among previously documented maternal determinants of neonatal bone mass in healthy pregnancies, maternal fat stores may mediate their effect on fetal bone accrual through variation in fetal leptin concentrations

Premature ovarian failure in androgen receptor-deficient mice

Premature ovarian failure (POF) syndrome, an early decline of ovarian function in women, is frequently associated with X chromosome abnormalities ranging from various Xq deletions to complete loss of one of the X chromosomes. However, the genetic locus responsible for the POF remains unknown, and no candidate gene has been identified. Using the Cre/LoxP system, we have disrupted the mouse X chromosome androgen receptor (Ar) gene. Female AR(–/–) mice appeared normal but developed the POF phenotype with aberrant ovarian gene expression. Eight-week-old female AR(–/–) mice are fertile, but they have lower follicle numbers and impaired mammary development, and they produce only half of the normal number of pups per litter. Forty-week-old AR(–/–) mice are infertile because of complete loss of follicles. Genome-wide microarray analysis of mRNA from AR(–/–) ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by AR. Our findings suggest that AR function is required for normal female reproduction, particularly folliculogenesis, and that AR is a potential therapeutic target in POF syndrome