This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 ...years, range 0-16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (AR) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the AR gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the AR gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.
In this exposition a novel feasible version of traditional discretization methods for linear semi-infinite programming problems is presented. It will be shown that each - usually infeasible - iterate ...can be easily supplemented with a feasible iterate based on the knowledge of a Slater point. The effectiveness of the method is demonstrated on the problem of finding model free bounds to basket option prices which has gained a significant interest in the last years. For this purpose a fresh look is taken on the upper bound problem and on some of its structure, which needs to be exploited to yield an efficient solution by the feasible discretization method. The presented approach allows the generalization of the problem setting by including exotic options (like power options, log-contracts, binary options, etc.) within the super-replicating portfolio.
Management of disorders of sex development Hiort, Olaf; Birnbaum, Wiebke; Marshall, Louise ...
Nature reviews. Endocrinology,
09/2014, Letnik:
10, Številka:
9
Journal Article
Recenzirano
The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the ...development of the urogenital tract and reproductive system. A variety of genetic factors have been identified that affect sex development during gonadal differentiation or in specific disorders associated with altered androgen biosynthesis or action. The diagnosis of DSDs in individuals and the subsequent management of patients and their families requires a targeted and structured approach, involving a multidisciplinary team with effective communication between the disciplines. This approach includes distinct clinical, imaging, laboratory and genetic evaluations of patients with DSDs. Although treatment of patients with DSDs can include endocrine and surgical options, many patients have concerns that arise from past incorrect treatments that were founded on the traditional binary concept of the sexes. To dispel these concerns, it is necessary to create centres of expertise for DSDs that include physicians, surgeons, psychologists and specialists in diagnostic procedures to manage patients and their families. Additionally, the inclusion of trained peer support in the multidisciplinary DSD team seems to be integral to the supportive management of patients with DSDs. Most importantly, dealing with DSDs requires acceptance of the fact that deviation from the traditional definitions of gender is not necessarily pathologic.
CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction and visceral and ...subcutaneous fat distribution; however, the underlying pathological mechanisms remain unknown. We aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. At 4-6 months, CYP17A1-deficient mice were viable, with a KO:Het:WT ratio approximating the expected Mendelian ratio of 1:2:1. All Cyp17a1 knockout (KO) mice were phenotypically female; however, 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Both male and female homozygous KO mice were infertile, due to abnormal genital organs. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice and marked accumulation of progesterone in XX-KO mice. Elevated corticosterone levels were observed in both XY and XX KO mice. In addition, Cyp17a1 heterozygous mice were also backcrossed onto an Apoe KO atherogenic background and fed a western-type diet (WTD) to study the effects of CYP17A1 on atherosclerosis. Cyp17a1 x Apoe double KO XY mice developed more atherosclerotic lesions than Apoe KO male controls, regardless of diet (standard or WTD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. In mice, CYP17A1 deficiency interferes with sex differentiation. Our data also demonstrate its key role in lipidomic profile, and as a risk factor in the pathogenesis of atherosclerosis.
Context:
Disorders characterized by PTH resistance are grouped within the term pseudohypoparathyroidism type I (PHPI). Most subtypes of this disease are caused by genetic or epigenetic changes of the ...GNAS locus leading to deficiency of the α-subunit of stimulatory G proteins (Gsα). Because the in vitro measured Gsα protein activity is normal in pseudohypoparathyroidism Ic (PHPIc), it had previously been postulated that this subtype is caused by impairment of distinct components of the G protein-signaling pathway. However, recently, pathogenic GNAS mutations in a subset of PHPIc patients were found.
Objective:
To clarify the underlying pathogenic mechanism of GNAS exon 1–13 mutation-negative PHPIc cases by investigating the differentially methylated regions of GNAS for epigenetic abnormalities.
Patients and Methods:
The methylation pattern of GNAS exons A/B, AS, XL, and NESP from blood-derived leukocytes of 26 PHPIc patients was assessed by pyrosequencing of bisulfite-converted DNA.
Results:
Six patients presented with three different patterns of epigenetic changes. One patient had an exclusive loss of methylation of exon A/B associated with a STX16 deletion; four patients had an additional loss of methylation in XL and AS and a gain of methylation in NESP; and one patient presented with partial GNAS methylation changes concerning all differentially methylated regions.
Conclusions:
Our results confirm that PHPIc is a heterogeneous entity caused in part by impaired Gsα function, not only due to mutations, but also due to abnormal imprinting of GNAS. However, in the majority of cases of PHPIc, the underlying etiopathogenesis remains elusive.
Zusammenfassung
Der lagerlose reluktante Rotations-Linear-Motor ist ein neuartiger Antrieb und ermöglicht unabhängig voneinander sowohl magnetisches Schweben als auch Translation und Rotation eines ...ferromagnetischen Rotors. Zusammen mit der kompakten, einfachen und robusten Bauform ermöglicht dieser Motor ein großes Spektrum an neuen Einsatzgebieten. Durch die große Vielfalt an Bewegungsmöglichkeiten und die Verkopplungen vieler physikalischer Größen des Systems ist die benötigte Regelung der Rotorlage in allen sechs Freiheitsgraden wesentlich komplexer als die Regelung konventioneller Antriebe. Es wurde daher zunächst eine theoretische Modellbildung des Motors mit geeigneten Vereinfachungen durchgeführt. Anschließend wurde eine Basisvariante der Regelung der Rotorlage in allen sechs Freiheitsgraden entwickelt, mit der der Motor erfolgreich vollständig in Betrieb genommen werden konnte. Unter Nutzung dieser Regelung wurden erste Untersuchungen zur Dynamik des Gesamtsystems mittels Auswertung der Systemantworten auf verschiedene Sollwertsprünge durchgeführt.
Zusammenfassung
Der lagerlose reluktante Rotations-Linear-Motor ist ein neuartiger Antrieb und ermöglicht unabhängig voneinander sowohl magnetisches Schweben als auch Translation und Rotation eines ...ferromagnetischen Rotors. Zusammen mit der einfachen und robusten Bauweise in Form eines kompakten Aktuators mit Doppelstator ermöglicht dieser Motor ein großes Spektrum an neuen Einsatzgebieten. Für Translation mit langen Verfahrwegen und eine hohe Ausnutzung der Maschine wird eine spezielle zweidimensionale Verzahnung von Rotor und Stator benötigt. Es wurden verschiedene Verzahnungstypen mit gleicher Nutteilung in Stator und Rotor untersucht, die sich in die zwei Grundtypen Schachbrettverzahnung und Kreuzverzahnung einteilen lassen. Für diese erfolgten eine Analyse und ein Vergleich der erreichbaren Kraftdichten für einen magnetischen Pol der Maschine. Die Schachbrettverzahnung erreicht dabei eine deutlich höhere Tangentialkraftdichte bei nur geringfügig niedrigerer Radialkraftdichte. Im Gegensatz zur Kreuzverzahnung sind jedoch beide Tangentialkräfte verkoppelt. Für die Ermittlung der optimalen Verzahnungsversetzungen und den Nachweis der Steuerbarkeit wurde eine Minimierung einer Zielfunktion, welche die Stromwärmeverluste im ungünstigsten Fall widerspiegelt, durchgeführt. Anhand der jeweils minimalen Zielfunktionswerte konnte gezeigt werden, dass sowohl ein schachbrettverzahnter Motor als auch ein kreuzverzahnter Motor mit sechs Polpaaren steuerbar ist. Die erreichbaren Tangentialkräfte des schachbrettverzahnten Motors liegen deutlich über jenen des kreuzverzahnten Motors, die Radialkräfte sind nur geringfügig niedriger.
In humans, mutations of Desert Hedgehog gene (DHH) have been described in patients with 46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy. In this study, we describe two patients ...diagnosed with GD, both harboring novel DHH compound heterozygous mutations p.Tyr176*;Asn337Lysfs*24 and p.Tyr176*;Glu212Lys. To investigate the functional consequences of p.(Asn337Lysfs*24) and p.(Glu212Lys) mutations, located within the C‐terminal part of DHh on auto‐processing, we performed in vitro cleavage assays of these proteins in comparison with Drosophila melanogaster Hedgehog (Hh). We found that p.(Glu212Lys) mutation retained 50% of its activity and led to a partially abolished DHh auto‐processing. In contrast, p.(Asn337Lysfs*24) mutation resulted in a complete absence of auto‐proteolysis. Furthermore, we found a different auto‐processing profile between Drosophila Hh and human DHh, which suggests differences in the processing mechanism between the two species. Review of the literature shows that proven polyneuropathy and GD is associated with complete disruption of DHh‐N, whereas disruption of the DHh auto‐processing is only described with GD. We propose a model that may explain the differences between Schwann and Leydig cell development by autocrine versus paracrine DHh signaling. To our knowledge, this is the first study investigating the effect of DHH mutations on DHh in vitro auto‐processing.
We describe two patients diagnosed with GD, both harboring novel DHH compound heterozygous mutations p.Tyr176*;Asn337Lysfs*24 and p.Tyr176*;Glu212Lys. To investigate the functional consequences of p.(Asn337Lysfs*24) and p.(Glu212Lys) mutations, we performed in vitro cleavage assays of these proteins in comparison to Drosophila melanogaster Hedgehog (Hh). While p.(Glu212Lys) retained 50% of its activity and led to a partially abolished DHh auto‐processing, p.(Asn337Lysfs*24) resulted in a complete absence of auto‐proteolysis. Furthermore, we found a different auto‐processing profile between Drosophila Hh and human DHh.
Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and ...limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss‐of‐function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4‐year‐old girl with features reminiscent of CdLS. Patient B, a 15‐year‐old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.
PDF
