ABSTRACT GLI3 is the gene responsible for Greig cephalopolysyndactyly syndrome (GCPS), Pallister–Hall syndrome (PHS) and Postaxial polydactyly type-A (PAP-A). Genetic polydactyly mice such as Pdn/Pdn (Polydactyly Nagoya), XtH/XtH (Extra toes) and XtJ/XtJ (Extra toes Jackson) are the mouse homolog of GCPS, and Gli3tmlUrtt/Gli3tmlUrt is produced as the mouse homolog of PHS. In the present review, relationships between mutation points of GLI3 and Gli3, and resulting phenotypes in humans and mice are described. It has been confirmed that mutation in the upstream or within the zinc finger domain of the GLI3 gene induces GCPS; that in the post-zinc finger region including the protease cleavage site induces PHS; and that in the downstream of the GLI3 gene induces PAP-A. A mimicking phenomenon was observed in the mouse homolog. Therefore, human GLI3 and mouse Gli3 genes have a common structure, and it is suggested here that mutations in the same functional regions produce similar phenotypes in human and mice. The most important issue might be that GCPS and PHS exhibit an autosomal dominant trait, but mouse homologs, such as Pdn/Pdn, XtH/XtH, XtJ/XtJ and Gli3tmlUrt/Gli3tmlUrt, are autosomal recessive traits in the manifestation of similar phenotypes to human diseases. It is discussed here how the reduced amounts of the GLI3 protein, or truncated mutant GLI3 protein, disrupt development of the limbs, head and face.
ABSTRACT Abnormal heart development causes various congenital heart defects. Recent cardiovascular biology studies have elucidated the morphological mechanisms involved in normal and abnormal heart development. The primitive heart tube originates from the lateral-most part of the heart forming mesoderm and mainly gives rise to the left ventricle. Then, during the cardiac looping, the outflow tract is elongated by the addition of cardiogenic cells from the both pharyngeal and splanchnic mesoderm (corresponding to anterior and secondary heart field, respectively), which originate from the mediocaudal region of the heart forming mesoderm and are later located anteriorly (rostrally) to the dorsal region of the heart tube. Therefore, the heart progenitors that contribute to the outflow tract region are distinct from those that form the left ventricle. The knowledge that there are two different lineages of heart progenitors in the four-chambered heart provides new understanding of the morphological and molecular etiology of conotruncal heart defects.
ABSTRACT Constipation is a common pathological condition in pregnant women; nevertheless, its possible association with structural birth defects (i.e. congenital abnormalities [CA]) in their offspring has not been studied in controlled epidemiological studies. We evaluated the possible association between severe constipation with laxative treatment in pregnant women and congenital abnormalities in their offspring. The dataset of the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities (HCCSCA) 1980–1996 contained 22 843 cases with CA and 38 151 matched controls without CA. Only pregnant women with prospectively and medically recorded constipation were included in the study and 13 CA groups were compared in cases and all their matched controls. A total of 78 (0.34%) cases had mothers with severe constipation and treatment during pregnancy compared to 144 (0.38%) controls (adjusted OR with 95% CI = 1.0, 0.7–1.3). Specified groups of CA were also assessed versus controls, but a higher occurrence of pregnant women with severe constipation and related treatment was not found in any CA group. Among laxative drugs, senna has no teratogenic potential; thus, if severe constipation requires laxative drug treatment in pregnant women, senna is not contraindicated. A higher rate of CA was not found in the offspring of pregnant women with severe constipation and related senna treatment.
ABSTRACT To clarify the role of biotin in palatal formation, we investigated the effects of biotin deficiency on the development of palatal processes in mouse fetuses at midgestation. We also investigated protein expressions in the palatal processes. Pregnant mice were given either a biotin-deficient diet or a biotin-supplemented (control) diet from day 0 of gestation (dg 0). Some dams in the biotin-deficient group were changed to a biotin-supplemented diet on dg 12, 13 or 14. On dg 15, the palatal processes were dissected from these fetuses and their peptides were characterized using two-dimensional electrophoresis and liquid chromatography/tandem mass spectrometry (LC-MS/MS) system. Regarding Trasler's stage for the growth of the palatal processes in mouse fetuses on dg 15, the average stage of palatal development was 5.83 ± 0.39 in the biotin-supplemented group, 5.39 ± 0.66 in the dg 13-supplemented group, and 4.64 ± 0.90 in the biotin-deficient group. The development of the palatal processes significantly increased in relation to the earlier day of biotin supplementation. In a protein analysis of palatal processes by isoelectro focusing (IEF) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), a 19-kDa spot was confirmed around position at pI 6–7 in the biotin-supplemented group, but this protein was not present in either the biotin-deficient group or the dg 13-supplemented group. From the MS/MS database of peptides, adenosine diphosphate (ADP)-ribosylation factor 2 (arf2) and α-crystallin were detected in the mesenchyme of the palatal processes. It is suggested that the expression of these proteins may be downregulated by biotin deficiency, inducing the inhibited development of palatal processes.
ABSTRACT Genetic polydactyly/arhinencephaly mouse embryo, Pdn/Pdn, exhibits suppression of Gli3 gene expression. Ochratoxin A (OTA) is a teratogen that causes neural tube defects (NTD) in mice. We investigated gender-dependent differences in the incidence of NTD induced by OTA in the Pdn/Pdn mouse. After administering 2 mg/kg OTA to Pdn/+ female mice, mated with Pdn/+ males, on day 7.5 of gestation, we examined the genotypes, sex and NTD of fetuses on day 18. Non-treated Pdn/Pdn had a 15.8% risk of NTD, and all NTD fetuses were female. When Pdn/Pdn embryos were exposed to OTA, the incidence of NTD increased to 16 (51.6%) of 31 Pdn/Pdn fetuses, and 10 (71.4%) of 14 male Pdn/Pdn fetuses exhibited NTD. From these results, it was speculated that NTD in OTA-treated male Pdn/Pdn were due to the synergistic effect between depressed Gli3 and altered sex-correlated gene expression from OTA treatment. After treatment with OTA, the embryos were recovered on day 9 and gene expressions, which were correlated with Gli3, telencephalic morphogenesis, formation of gonadal anlage, and gender-dependent differentiation were investigated. From real-time polymerase chain reaction analysis results, it was suggested that the manifestation of NTD in the male OTA-treated Pdn/Pdn might be due to the complicated altered gene expressions among Gli3, Wnt7b, Wnt8b, Fez1, Barx1, Lim1, Dmrt1, Igf1, Fog2, Dax1 and Sox9, and in particular, upregulation and gender-dependent difference in Barx1 and gender-dependent difference in Sox9 gene expressions might be noteworthy findings.
ABSTRACT XY females are rare individuals who carry a Y chromosome but are phenotypically female. In approximately 80–90% of these cases, there are no mutations in the SRY gene, a testis-determining gene on the short arm of the Y chromosome, and the pathophysiology of XY females without SRY mutation remains unclear. In the present study, we used a molecular data mining technique to analyze the pathophysiology of an XY female with functional SRY and pericentric inversion of the Y chromosome, and compared the results with those of a normal male. Interestingly, upregulations of numerous genes included in the development category of the Biological Process ontology, including genes associated with sex determination and organ morphogenesis, were seen in the patient. Additionally, the transforming growth factor-β (TGF-β) signaling pathway and Wnt signaling pathway, in which most cell–cell interactions during embryonic development are involved, were altered. Alterations in the expression of numerous genes at the developmental stage, including alterations at both the gene and pathway levels, may persist as a vestige of anomalies of sex differentiation that presumably began in the fetal period. The present study indicates that a data mining technique using bioinformatics contributes to identification of not only genes responsible for birth defects, but also disorders of sex development (DSD)-specific pathways, and that this kind of analysis is an important tool for clarifying the pathophysiology of human idiopathic XY gonadal dysgenesis. Our findings could serve as one of the basic datasets which will be used for future follow-up investigations.
ABSTRACT The aim of the present study was to develop a quantitative evaluation method for detecting antiandrogenic activity of chemicals in rabbits that are regularly used for developmental toxicity studies. Kbl: New Zealand White rabbits (n = 8–9) were injected intramuscularly with an antiandrogen, cyproterone acetate (CA; 10 mg/kg body weight [BW]/day), on gestation days (GD) 13–24. On GD 29, live fetuses were obtained by cesarean section and sexed by examination of the internal genitalia. The external genitalia were evaluated in cross-section measurements of the phallus by both diameter and width of the ventral gap of the preputial lamella with a micrometer under a stereoscopic microscope. The diameters of the preputial lamella were 1015 ± 83.5, 856 ± 64.0, and 865 ± 72.6 µm in control males, control females, and CA-treated males, respectively. The ventral gaps of the preputial lamella were 26 ± 8.2, 437 ± 72.3, and 318 ± 59.4 µm in the control males, control females, and CA-treated males, respectively. There were statistically significant differences in both parameters between control males and control females or CA-treated males. The lower fetal BW in CA-treated males did not disturb the detection of the feminization of the ventral gap of the preputial lamella; however, the diameter of the preputial lamella might be influenced by fetal BW because no difference in the relative diameter of the preputial lamella was found between control males and CA-treated males.
These results demonstrated that this approach could detect the antiandrogen activity of CA quantitatively by feminization of male external genitalia in rabbit fetuses.
ABSTRACT Environmental enrichment (EE) facilitates recovery from behavioral abnormalities and spatial memory disabilities in several neurological disease models. Exposure to EE improves spatial memory acquisition and enhances the survival of newly generated cells in the dentate gyri of adult rodents. However, the effects of EE on spatial learning and neurogenesis in the methylazoxymethanol acetate-induced microencephalic rat have not been investigated. Depletion of serotonin in the rat hippocampus is known to influence spatial memory and adult neurogenesis, suggesting a role for serotonin in these processes. To confirm this hypothesis, male methylazoxymethanol acetate-induced microencephalic rats were exposed to EE or conventional housing after weaning; half of these rats further received intracisternal 5,7-dihydroxytryptamine on postnatal day 3, to induce long-lasting depletion of serotonin. As adults, these microencephalic rats were observed using the Morris water maze test and examined for hippocampal neurogenesis. EE alleviated the impairment of spatial memory acquisition and enhanced neurogenesis in the dentate gyri of adult microencephalic rats. Injection of 5,7-dihydroxytryptamine during the neonatal period caused pronounced reductions in hippocampal serotonin levels in these rats. Long-lasting depletion of serotonin eliminated the EE-induced alleviation of spatial memory acquisition and neurogenesis impairment in microencephalic rats. The present results suggest that EE alleviates spatial memory performance deficits in microencephalic rats and further indicate that serotonin might be involved in the underlying mechanisms through increased hippocampal neurogenesis. These data provide new insights into therapeutic interventions for individuals with human migration disorders associated with learning disabilities.
ABSTRACT Six pediatric cases including four infants with congenital polymicrogyria including the perisylvian region are presented herein. Their clinical features were analyzed and compared with patients suffering from congenital bilateral perisylvian syndrome (CBPS). Two specific abnormalities were diagnosed as accompanying disorders in two cases, namely Kabuki syndrome and Peters' anomaly. In the other four cases, the pathogenetic etiology was not elucidated. Subtle symptoms, such as choking and drooling became detectable in one case each, and expressive language development was delayed in two patients. A developmental delay became apparent in five cases during the follow-up period, and epilepsy was observed in one patient with onset at 12 years of age. Our results indicate that the presence of perisylvian polymicrogyria may not always result in the development of oropharyngoglossal dysfunction or dysarthria, although most patients tend to gradually show the onset of developmental disorders. To support cognitive and psychosocial development, an early integrated approach, including not only conventional speech and language therapy, but also various communication methods is essential for patients with congenital polymicrogyria including the perisylvian region.
ABSTRACT The pinna is the second most common site for external ear vascular malformation in the head and neck. These malformations are relatively uncommon in adults and can pose difficult therapeutic challenges. We hereby present a case of a 69-year-old man with a congenital lesion in the right pinna consistent with an arteriovenous malformation. The lesion was complicated by ulceration and bleeding for 6 months prior to presentation. Resection of pinna was carried out, and satisfactory functional and esthetic results were obtained. There was no recurrence at 22 months of regular follow up.
ABSTRACT A 20-year-old man with bilateral absence of patella, thinness of the left femoral neck, femoral and tibial shaft was reported. This clinical presentation has not been reported in the English language literature. We propose that the unusual association observed in our patient may represent a distinguishing clinical presentation from previously reported aplastic patella syndromes.