ABSTRACT Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations of either of the two tumor suppressor genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. TSC is pathologically characterized by the occurrence of multiple hamartias (focal dysplasias) and hamartomas (benign tumors) in the brain and many other organs. Cortical tubers are hamartias in the cerebral cortex responsible for many neuropsychiatric symptoms of TSC. Unlike TSC-associated hamartomas, cortical tubers do not result from second somatic mutations of the TSC gene, and the mechanism by which they occur remains obscure. Histologically, the most conspicuous feature of cortical tubers is the presence of abnormal giant cells, which show abnormal size and differentiation. Recent studies on human TSC and its animal models have elucidated the critical roles of hamartin and tuberin regulating the growth and differentiation of neural cells.
ABSTRACT To evaluate the role of cobalamin (Cbl) on spermatogenesis, the effect of dietary vitamin B12 deficiency on early spermatogenesis was histologically investigated in male fetuses and newborns in the first filial generation (F1 males) of rats. There was no difference in the number of gonocytes and supporting cells of Sertoli in the gonad in male fetuses on day 16 of gestation and in the testes in F1 males at 0 days of age between vitamin B12-deficient (VB12-D) and vitamin B12-supplemented (VB12-S) groups. However, at 21 days of age, a decreased number of spermatogonia and no spermatocytes were observed in the VB12-D group. Numerous TUNEL positive cells were located among spermatocytes of the spermatogenic epithelium. The ultrastructural features examined using transmission electron microscopy were considered to be indicative of apoptosis. The incidence of seminiferous tubules having apoptotic cells was 51.5% in the VB12-D group. At 60 days of age, aplasia of the spermatids and spermatozoa was detected in the VB12-D group. In the connective tissue between the seminiferous tubules, many interstitial Leydig cells and blood vessels were observed in the VB12-D group, as compared with the VB12-S group. These changes produced by vitamin B12 deficiency can be reversed by providing a VB12-S diet after weaning at 21 days of age. From these findings, such a vitamin B12 deficiency during gestation and lactation could affect the germ cells and especially damage spermatocytes in F1 male rats, which indicates that Cbl may be an essential constituent in the meiosis of spermatogenesis.
ABSTRACT The objective of this study was to investigate the human teratogenic potential of oral prenoxdiazine treatment during pregnancy. The analysis of cases with congenital abnormalities and their matched controls without congenital abnormalities was performed in the large population-based data set of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996. Of the 22 843 pregnant women who had offspring with congenital abnormalities, 158 (0.7%) were treated with prenoxdiazine. Of the 38 151 pregnant women who had babies without any defects in the study period (control group), 226 (0.6%) were treated with prenoxdiazine (adjusted prevalence odds ratio, 1.0; 95% confidence interval, 0.8–1.3). The comparison of cases and their matched controls did not show a significantly higher rate of prenoxdiazine treatment during the second and third months of gestation in the total (adjusted prevalence odds ratio, 1.4; 95% confidence interval, 0.9–2.2) or in any group of congenital abnormalities. Treatment with prenoxdiazine during pregnancy did not have any teratogenic risk to the fetus. Thus, prenoxdiazine treatment in pregnant women with an unproductive cough may be beneficial.
ABSTRACT Erythropoietin, by binding to its receptor, stimulates definitive erythroblasts to accumulate hemoglobin (Hb) by up-regulating erythroid-specific genes and causes differentiation of erythroblasts into erythrocytes. In mouse decidua we have found the expression of transcripts for the erythropoietin receptor, the function of which has not yet been elucidated. Erythropoietin signaling was inhibited by the injection of a soluble form of the erythropoietin receptor capable of binding with erythropoietin into the mouse uterine cavity on day 4 of gestation, and pale and defective decidual bodies appeared three days later. These pale decidual bodies contained defective embryos without extension to the ectoplacental region, while normal reddish decidual bodies contained normal developing embryos and expressed embryonic and adult Hb with characteristic location of the respective hemoglobins in which an ɛ- or β-globin signal was confirmed. Furthermore, blocking of erythropoietin signaling destroyed Hb-containing cells and resulted in apoptosis that caused embryonic death. Thus, erythropoietin-mediated Hb synthesis is essential for the survival of decidual cells. In addition, although no transcripts for GATA-1 and erythroid heme enzymes could be detected, genes for β-globin, as well as non-specific δ-aminolevulinate synthase, were expressed and regulated in an erythropoietin-dependent manner. This is the first evidence that ectopic Hb synthesis exists and that erythropoietin coregulates erythroid (globin) and nonerythroid (δ-aminolevulinate synthase) genes.
ABSTRACT Congenital hypoplasia and dysplasia affect the postnatal development of organs, their physiological functioning in adulthood and the incidence of related diseases at an advanced age. Hypogonadic (hgn/hgn) rats are characterized by male sterility, reduced female fertility, progressive renal insufficiency and growth retardation, all controlled by a single recessive allele (hgn) located on chromosome 10. Since our previous studies indicated that the hypoplasia (dysplasia) of the affected organs was present at birth, we examined the embryonic pathogenesis. We mated hgn/hgn females to Brown Norway males and backcrossed F1 males to hgn/hgn females. The resulting N1 fetuses were genotyped using a hgn-linked microsatellite. Both sexes of hgn/hgn fetuses showed low body weight after embryonic day (ED) 15.5 and renal hypoplasia after ED 17.5. Their kidneys contained a reduced number of nephrons in a poorly formed nephrogenic zone and renal cortex. The hgn/hgn ovaries contained a small number of oogonia at ED 15.5 and oocytes after ED 17.5. Testicular growth defects were obvious after ED 17.5, and reduced numbers of Sertoli cells were detected at ED 19.5 and 21.5. The seminiferous cords in hgn/hgn testes contained more apoptotic and mitotic cells than those in +/hgn testes. These findings suggest that the phenotypes described in adult hgn/hgn rats result from embryonic hypogenesis, which continues to early postnatal stage and causes a reduction in functional tissues and cells. Since hgn/hgn rats have an insertion mutation in the microtubule-associated protein Spag5 gene, the embryonic hypogenesis described in hgn/hgn rats might result from defective cell proliferation.
ABSTRACT Failed ultrasonographic visualization of nasal bones is associated with an increased risk of fetal malformations. Maternal ethnicity and chromosomal abnormalities influence the incidence and visualization rate of nasal bones. A case of absent nasal bones with fronto-nasal dysplasia and septated cystic hygroma identified at 13+5 weeks’ gestation in a trisomy 18 fetus is reported. The crown–rump length was 82 mm and the absent nasal bones were associated with micrognathia and a flattened face. The risks for trisomy 21 and 18 were subsequently calculated. The couple refused chorionic villus sampling. At 19 weeks’ gestation a follow-up scan revealed, apart from the resolution of septated cystic hygroma, hypertelorism, a large interventricular septum defect with an atrio-ventricular canal and an abnormal A wave Doppler pulsation at the level of the ductus venosus. Bilateral choroid plexus cysts were additional ultrasound findings. At that time, an uneventful cordocentesis was performed showing a 47,XY(+18) karyotype. Termination of pregnancy was achieved and pathologic examination confirmed the ultrasonographically detected fetal malformations. When screening the fetal face for the presence or absence of nasal bones during the first trimester pregnancy scan the following points must be taken into consideration: (i) the ethnicity of the mother; (ii) if the nasal bones are absent, measurement of nuchal translucency and risk calculations for trisomy 21 and trisomy 18 should be performed; (iii) if the calculated risks are high, karyotyping should be recommended; and (iv) determine whether the absent nasal bones are an isolated or an associated finding and, in the latter case, discriminate between minor or major fetal malformations.
ABSTRACT Craniofrontonasal syndrome (CFNS) is characterized by craniosynostosis, hypertelorism, a broad nasal tip and occasionally cleft lip and palate, and is caused by a mutation in the ephrin-B1 gene (EFNB1). The study of naturally occurring human EFNB1 mutations offers a unique opportunity to better define the critical portion within the ephrin domain that is essential for the function of EFNB1 protein in craniofacial development. Here, we report a CFNS patient with a novel EFNB1 missense mutation present at the interface between EFNB1 and its receptor proteins. The patient’s facial features included hypertelorism, a broad nasal tip, brachycephaly, frontal bossing, facial asymmetry and esotropia. In addition, she had pectus carinatum, grooved nails on her thumb, an abnormal palmar crease pattern and a broad first toe. Her development was appropriate for her age. Direct sequencing of polymerase chain reaction products using an autosequencer revealed a heterozygous missense mutation, Ser118Ile. Ser118 is located in the G-H loop of the extracellular ephrin domain and is highly evolutionarily conserved among rodents, avians and fish. The mutation occurred de novo and was not present in 100 normal Japanese control subjects. Substitutions of the adjacent amino acid residue, Pro119, have been previously reported in three CFNS patients. Since the structure of EFNB1 is not yet available, the spatial locality of Ser118 was characterized using the protein structure of EFNB2. We deduced that Ser118 in EFNB1 resides at the major dimerization interface with Eph receptors and inferred that the Ser118Ile mutation may impede the protrusion of the G-H loop, thereby disturbing Eph–Ephrin signal transduction.