Molecular genetic and cytogenetic characterization of a partial Xp duplication and Xq deletion in a patient with premature ovarian failure.

BACKGROUND: The etiology of premature ovarian failure (POF) still remains undefined. Although the majority of clinical cases are idiopathic, there are possibilities of the underestimation of the most common etiologies, probably genetic causes. By reporting a case of POF with a partial Xp duplication and Xq deletion in spite of a cytogenetically 46,XX normal karyotype, we look forward that the genetic cause of POF will be investigated more methodically. METHODS: We performed a basic and clinical study at a university hospital-affiliated fertility center. The study population was a POF patient and her family. Cytogenetic analysis, FMR1 gene analysis, multiplex ligation-dependent probe amplification (MLPA), fluorescent in situ hybridization (FISH), and oligonucleotide-array based comparative genomic hybridization (array CGH) were performed. RESULTS: In spite of normal cytogenetic analysis in the proband and her mother and younger sister, FMR1 gene was not detected in the proband and her younger sister. In Southern blot analysis, the mother showed a normal female band pattern, but the proband and her younger sister showed no 5.2kb methylated band. The abnormal X chromosome of the proband and her sister was generated from the recombination of an inverted X chromosome of the mother during maternal meiosis, and the karyotype of the proband was 46,XX,rec(X)dup(Xp)inv(X)(p22.1q27.3). CONCLUSION: Array CGH followed by FISH allowed precise characterization of the der(X) chromosome and the initial karyotype of the proband had been changed to 46,XX,rec(X)dup(Xp)inv(X)(p22.3q27.3)mat.arr Xp22.33p22.31(216519-8923527)x3,Xq27.3q28(144986425-154881514)x1. This study suggests that further genetic investigation may be needed in the cases of POF with a cytogenetically 46,XX normal karyotype to find out the cause and solution for these disease entities.

Transcriptional profiling with a pathway-oriented analysis in the placental villi of unexplained miscarriage.

INTRODUCTION: Miscarriage is the most common placental-related complication of pregnancy. It has been extensively investigated to discover the underlying mechanism(s) by which miscarriage occurs, but in many cases the etiology still remains unclear. The aim of this study was to analyze genome-wide expression profiles of placental villi (PV) from unexplained miscarriage with a pathway-oriented method for identifying underlying mechanism(s) of unexplained miscarriage. METHODS: We investigated PV of 18 women with unexplained miscarriage and 11 women underwent normal pregnancy. Each PV was obtained through dilatation & evacuation and chorionic villous sampling, respectively. Genome-wide expression profiles of PV were analyzed by Gene Set Enrichment Analysis (GSEA) to find dysregulated signaling pathways in PV of unexplained miscarriage. RESULTS: Unsupervised hierarchical clustering showed heterogeneity of expression profiles between PV of normal developing pregnancy and unexplained miscarriage. GSEA, a supervised analysis, with KEGG pathways revealed that several gene sets associated with mitochondrial function including glutathione metabolism and oxidative phosphorylation are dysregulated in PV from unexplained miscarriage. RT-PCR, real-time RT-PCR and/or immunohistochemistry reinforced that expression of genes constituting these gene sets enriched in normal pregnancy and Cu/Zn-superoxide dismutase was down-regulated in PV of unexplained miscarriage. DISCUSSION: Structural vulnerability of placental villi for reactive oxygen species (ROS), which is caused by systemic down-regulation of mitochondrial pathways involved in mitochondrial redox balance and functions, aggravates oxidative stress with increased ROS production in PV of unexplained miscarriage. CONCLUSION: Systemic vulnerability for ROS in PV could be a major cause of unexplained miscarriage.

SRY-negative 46,XX infertile male with Leydig cell hyperplasia: clinical, cytogenetic, and molecular analysis and review of the literature.

OBJECTIVE: To describe a 46,XX male whose infertility is not accounted for by a translocation of the SRY gene to the X chromosome or to the autosomes. DESIGN: Case report. SETTING: Fertility Center of CHA Gangnam Medical Center, Seoul, South Korea. PATIENT(S): A 29-year-old male with normal male phenotype, in whom seminal analysis showed complete azoospermia. INTERVENTION(S): Laboratory evaluations, radiologic studies, testicular biopsy, G-banding karyotype, in situ fluorescence hybridization, and polymerase chain reaction. MAIN OUTCOME MEASURE(S): Clinical and laboratory findings. RESULT(S): Peripheral blood culture for chromosome studies revealed 46,XX chromosome complement. Cytogenetic and molecular analyses excluded the presence of SRY gene. Radiologic studies displayed male structures without Müllerian ducts. Gonadal biopsy showed testicular Leydig cell hyperplasia. CONCLUSION(S): This is a very rare case of testicular differentiation in a 46,XX chromosomal constitution without SRY. This finding suggests that some unknown genes downstream participate in sex determination.