Katarzyna Jarzabek

A case of complete hypogonadotropic hypogonadism with a mutation in the gonadotropin-releasing hormone receptor gene

OBJECTIVE To screen for mutations in the GnRH receptor gene in a case of complete hypogonadotropic hypogonadism (HH) with GnRH resistance. DESIGN Case report. SETTING A university hospital. PATIENT(S) A male patient with the complete form of HH without anosmia. INTERVENTION(S) Physical examination and laboratory and genetic studies. MAIN OUTCOME MEASURE(S) Gonadotropins at the basal state and after GnRH administration and GnRH receptor DNA sequencing. RESULT(S) A novel missense mutation, localized in the first amino acid of the extracellular loop found in the heterozygous state, and another mutation, Arg(139)His (R139H), located in the conserved aspartate-arginine-serine motif at the junction of the third transmembrane and second intracellular loop of the GnRH receptor, were identified in the homozygous state. Pedigree studies reveal that both parents were heterozygous for R139H, while the mother carried the missense mutation at codon 1(M1T). CONCLUSION(S) GnRH receptor mutations may account for a larger proportion of cases of HH than previously thought. The phenotypic spectrum of HH seems to vary, and this heterogeneity may be related, at least in part, to the degree of impaired biological activity of the mutated GnRH receptor caused by the allelic type of mutations.

Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency.

CONTEXT Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes. OBJECTIVE The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles. SETTING This study was an international collaboration among academic medical centers. METHODS IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes, were identified from various academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry. RESULTS A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion. CONCLUSIONS We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.

The vitamin A family can significantly decrease the expression of ERβ of ERs positive breast cancer cells in the presence or absence of ER ligands and paclitaxel

Taxanes have high activity against breast cancer cells either as the single agent or in combination with other anticancer compounds. The aim of the study was to determine the effects of vitamin A compounds on the cytotoxic action of paclitaxel and on the expression of ERs in the MCF-7 breast cancer cells. Retinol and β-carotene, but not retinoids, added to the culture exerted an effect on paclitaxel activity. However, only β-carotene significantly reduced the percentage of proliferating cells (40.36% ± 5.64, p < 0.01). We observed that vitamin A and its derivatives combined with paclitaxel and estradiol decreased the percentage of proliferating cells, but only in comparison to estradiol group, whereas retinol and lycopene administered together with paclitaxel and tamoxifen decrease significantly the percentage of proliferatin cells (36.85% ± 4.71, p < 0.0001 and 37.22% ± 1.59, p < 0.0001 respectively, compared with paclitaxel group). We have shown that paclitaxel increases the expression of ERα and ERβ mRNA in MCF-7 line. The strongest effect of transcription inhibition ERα (2.5 times) and especially ERβ (10 times) was observed after addition of 9-cis retinoic acid and paclitaxel. This data suggests a synergistic effect of the compounds on ERβ down-regulation. Our results support the use of retinoid is treatment of ER positive breast cancer patients.

Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.