Expression of mRNA Mastermind-like Domain-containing 1, Androgen Receptor, and Estrogen Receptor in Patients with Hypospadias

BACKGROUND: Androgen (AR) and Estrogen (ER) hormones play an important role in the prenatal and postnatal development of the urogenital tract and especially the penis. Growth factors also influence the development of genital structures. Little is known about the exact role of Mastermind Like Domain 1 (MAMLD1) in sexual development. A role in sex differentiation through supporting testosterone production in critical periods of male development has been suggested. MAMLD1 mutations result in hypospadias with and without a disorder of sexual development (DSD) primarily because of compromised testosterone production around the critical period for fetal sex development, but the underlying etiology remains unclear. AIM: The objective of this study was to investigate the correlation between gene factor MAMLD1, AR, ER1, and ER2 with the incidence of hypospadias. OBJECTIVE: The objective of this study was to investigate the correlation between gene factor MAMLD1, AR, ER1, and ER2 with the incidence of hypospadias. METHODS: From 2017-2018, peri-urethral dartos were harvested from 46 patients with proximal hypospadias, 24 patients with distal hypospadias and 10 patients with normal penile were used as controls. The expressions of MAMLD1, AR, ER1, and ER2 were investigated by one-step quantitative polymerase chain reaction. RESULTS: Median age was 5 years old in the 70 patients with hypospadias and 6 years old in the control subjects. Total specimens taken included 24 distal penile, 46 proximal penile, and 10 normal penile specimens. We found decreasing MAMLD1 and AR expressions, but ER2 expression increased in patients with hypospadias compared to controls, which was statistically significant (p < 0.001). A positive correlation between MAMLD1 and AR was found in patients with hypospadias (r = 0.062; p = 0.038). CONCLUSIONS: Decreasing of MAMLD1 and AR expression was followed by increasing ER2 expression in patients with hypospadias. MAMLD1 had a positive correlation with AR so the defect of MAMLD1 may influence AR and increase the incidence of hypospadias.

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Psychological Problem in Pediatric Disorder of Sex Development Patient and Relatives

Open Access Indonesian Journal of Medical Reviews ◽

10.37275/oaijmr.v1i2.552 ◽

2021 ◽

Vol 1 (2) ◽

pp. 24-27

Author(s):

Erlangga Danu Saputro

Keyword(s):

Sexual Development ◽

Psychosocial Problems ◽

Psychological Problem ◽

Systematic Search ◽

Basic Data ◽

Disorder Of Sex Development ◽

Sex Development ◽

Disorder Of Sexual Development ◽

Counselling Program

Disorder of sexual development (DSD) is one of challenging disorder that has to be done clinically and physiologically. The patients and relatives may experience various psychosocial problems that have an impact on their live. The aim of this study is to look at psychological problem in children with DSD and their relatives. A systematic search was conducted in PubMed for articles representing information on psychological problem to the patient and their relatives. Relevant data were extracted and narratively reviewed. The result of this review can be used as basic data in the development of counselling program for the patients and their relatives.

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Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance

Frontiers in Endocrinology ◽

10.3389/fendo.2020.582516 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lele Li ◽

Fenqi Gao ◽

Lijun Fan ◽

Chang Su ◽

Xuejun Liang ◽

...

Keyword(s):

Sexual Development ◽

Disorders Of Sex Development ◽

Specific Gene ◽

Causative Role ◽

Sex Development ◽

Whole Exome ◽

Clinical Series ◽

Oligogenic Inheritance ◽

Mode Of Inheritance

Mastermind-like domain-containing 1 (MAMLD1) has been shown to play an important role in the process of sexual development and is associated with 46,XY disorders of sex development (DSDs). However, the causative role of MAMLD1 variations in DSDs remains disputable. In this study, we have described a clinical series on children from unrelated families with 46,XY DSD harbouring MAMLD1 variants. Whole exome sequencing (WES) was performed for each patient. WES data were filtered using common tools and disease customisation algorithms, including comparison against lists of known and candidate MAMLD1-related and DSD-related genes. Lastly, we investigated the hypothesis that MAMLD1-related DSD may follow an oligogenic mode of inheritance. Forty-three potentially deleterious/candidate variants of 18 genes (RET, CDH23, MYO7A, NOTCH2, MAML1, MAML2, CYP1A1, WNT9B, GLI2, GLI3, MAML3, WNT9A, FRAS1, PIK3R3, FREM2, PTPN11, EVC, and FLNA) were identified, which may have contributed to the patient phenotypes. MYO7A was the most commonly identified gene. Specific gene combinations were also identified. In the interactome analysis, MAMLD1 exhibited direct connection with MAML1/2/3 and NOTCH1/2. Through NOTCH1/2, the following eight genes were shown to be associated with MAMLD1:WNT9A/9B, GLI2/3, RET, FLNA, PTPN11, and EYA1. Our findings provide further evidence that individuals with MAMLD1-related 46,XY DSD could carry two or more variants of known DSD-related genes, and the phenotypic outcome of affected individuals might be determined by multiple genes.

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Psychological Problem in Pediatric Disorder of Sex Development Patient and Relatives

Open Access Indonesian Journal of Medical Reviews ◽

10.37275/oaijmr.v1i2.33 ◽

2021 ◽

Vol 1 (2) ◽

pp. 24-27

Author(s):

Erlangga Danu Saputro

Keyword(s):

Sexual Development ◽

Psychosocial Problems ◽

Psychological Problem ◽

Systematic Search ◽

Basic Data ◽

Disorder Of Sex Development ◽

Sex Development ◽

Disorder Of Sexual Development ◽

Counselling Program

Disorder of sexual development (DSD) is one of challenging disorder that has tobe done clinically and physiologically. The patients and relatives may experiencevarious psychosocial problems that have an impact on their live. The aim of thisstudy is to look at psychological problem in children with DSD and their relatives.A systematic search was conducted in PubMed for articles representinginformation on psychological problem to the patient and their relatives. Relevantdata were extracted and narratively reviewed. The result of this review can beused as basic data in the development of counselling program for the patientsand their relatives.

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Proximal Hypospadias Repair Outcomes in Patients with a Specific Disorder of Sexual Development Diagnosis

Advances in Urology ◽

10.1155/2012/708301 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 6

Author(s):

Blake W. Palmer ◽

William Reiner ◽

Brad P. Kropp

Keyword(s):

Sexual Development ◽

Disorders Of Sex Development ◽

Hypospadias Repair ◽

Urethral Meatus ◽

Proximal Hypospadias ◽

Sex Development ◽

Disorder Of Sexual Development ◽

Increased Risk ◽

The Mean ◽

Contemporary Study

Boys with undermasculinized external genital and/or 46,XY disorders of sex development (DSD) often receive masculinizing genitoplasty. Such procedures are done to correct ventral curvature of the phallus, reposition a proximally located urethral meatus, and cosmetically correct the appearance of labioscrotal folds. No studies to date have assessed if patients with a specific DSD diagnosis have worse outcomes for severe proximal hypospadias procedures or whether or not these patients require more extensive surgical maneuvers than severe proximal hypospadias patients without a specific DSD diagnosis. We retrospectively reviewed consecutive proximal hypospadias repairs performed at our institution from 1998 to 2010 and compared the anatomy, surgical technique required for repair, and outcomes in patients with and without a definitive DSD diagnosis. Boys with a specific DSD diagnosis do have significantly more atypical anatomy when undergoing proximal hypospadias masculinizing genitoplasties. They are more likely to require associated gonad procedures but do not have an increased risk of complications or number of surgeries when compared to other proximal hypospadias patients without a specific DSD diagnosis. The risk of complications is consistent with reports in the literature, and the mean number of procedures in this contemporary study is fewer than in historic reports.

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A Young Male with Female Reproductive System

Journal of Medicine ◽

10.3329/jom.v11i1.4276 ◽

1970 ◽

Vol 11 (1) ◽

pp. 63-66

Author(s):

Md Robed Amin ◽

Amit Das ◽

Md Murad Hossain ◽

Md Ferdous Zaman ◽

Ahmedul Kabir ◽

...

Keyword(s):

Sexual Development ◽

Reproductive System ◽

Sexual Differentiation ◽

Sex Differentiation ◽

Young Male ◽

Female Reproductive System ◽

Disorders Of Sexual Development ◽

Sex Development ◽

Male Phenotype ◽

Disorders Of Sexual Differentiation

Patients with disorders of sexual differentiation possess discordance among sex chromosomes, gonads, sex hormones, and phenotypic sex. The most common of the phenotypic sex disorder is due to defect in enzyme for synthesis of steroids in adrenal cortex. A spectrum of phenotypes is observed in these cases. Here we present a case with features of female reproductive system in his body with male phenotype. As there was no trace of male sexual organs in all investigations but physical habitus was exclusively male with abundance of hair distribution the case was diagnosed as disorder of sex development (DSD) - female pseodoharmaphroditism. Keywords: Sex Differentiation Disorder, Disorders of Sexual Development, Pseudohermaphroditism DOI:10.3329/jom.v11i1.4276 J Medicine 2010: 11: 63-66

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Chromosomal Disorders of Sex Development

10.1093/med/9780199329007.003.0023 ◽

2018 ◽

Author(s):

R. J McKinlay Gardner ◽

David J Amor

Keyword(s):

Sexual Development ◽

De Novo ◽

Chromosome Abnormality ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Sequential Process ◽

Chromosomal Disorders ◽

Sex Development ◽

Development Proceeds

Chromosomal sex is, for the most part, congruently XX female and XY male. The XX and XY embryo are built on a fundamentally similar outline plan, and only as development proceeds do certain modifications evolve. If at any point in this sequential process some genetic instruction is faulty, inappropriate, or cannot be acted on, the direction of anatomical sexual development may proceed imperfectly or completely incongruently. This chapter reviews the conditions of ambiguous/incomplete/indeterminate development of the internal and external genitalia, where the basis of this is a chromosome abnormality, usually of the X or the Y chromosome. The key role of the SRY male-determining gene in a number of these conditions is noted. The de novo or familial origin of these disorders is discussed, with particular reference to possible risks of recurrence.

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Ovotesticular disorder of sexual development due to gonosomal mosaicism

Problems of Endocrinology ◽

10.14341/probl201056242-46 ◽

2010 ◽

Vol 56 (2) ◽

pp. 42-46

Author(s):

N Iu Raĭgorodskaia ◽

D A Morozov ◽

V B Chernykh ◽

N V Bolotova ◽

D A Zharkov ◽

...

Keyword(s):

Surgical Treatment ◽

Genetic Analysis ◽

Sexual Identity ◽

Rare Variant ◽

Sexual Development ◽

Sex Chromosome ◽

Sex Differentiation ◽

Marker Chromosome ◽

Disorder Of Sexual Development ◽

Comprehensive Examination

This paper describes diagnosis and surgical treatment of a 3.5 year-old child who presented with abnormal sex differentiation resulting in the development of gonads into ovotestes. This disorder was provoked by a rare variant of mosaicism involving sex chromosome and characterized by the presence of an irregular marker chromosome. Additional genetic analysis allowed its origin to be determined: it was identified as Yp chromosome. Comprehensive examination yielded criteria for the choice of sexual identity and provided a basis for the surgical treatment in conformity with the gender being sought.

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Cholesterol contributes to male sex differentiation through its developmental role in androgen synthesis and hedgehog signaling

Endocrinology ◽

10.1210/endocr/bqab066 ◽

2021 ◽

Author(s):

Anbarasi Kothandapani ◽

Colin R Jefcoate ◽

Joan S Jorgensen

Keyword(s):

Hedgehog Signaling ◽

Functional Role ◽

Sex Differentiation ◽

Developmental Defects ◽

Androgen Synthesis ◽

Sex Development ◽

Developmental Role ◽

Male Sex ◽

Hh Signaling

Abstract Two specialized functions of cholesterol during fetal development include serving as a precursor to androgen synthesis and supporting hedgehog (HH) signaling activity. Androgens are produced by the testes to facilitate masculinization of the fetus. Recent evidence shows that intricate interactions between the HH and androgen signaling pathways are required for optimal male sex differentiation and defects of either can cause birth anomalies indicative of 46,XY male variations of sex development (VSD). Further, perturbations in cholesterol synthesis can cause developmental defects, including VSD, that phenocopy those caused by disrupted androgen or HH signaling, highlighting the functional role of cholesterol in promoting male sex differentiation. In this review, we focus on the role of cholesterol in systemic androgen and local HH signaling events during fetal masculinization and their collective contributions to pediatric VSD.

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Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires

10.26434/chemrxiv.9209180 ◽

2019 ◽

Author(s):

Bella Grigorenko ◽

Igor Polyakov ◽

Alexander Nemukhin

Keyword(s):

Adenylyl Cyclase ◽

Bond Cleavage ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Md Simulations ◽

Coordination Shell ◽

Energy Profile ◽

One Step ◽

Type V

We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. Several stable six-fold coordination shells of MgA2+ are observed in MD simulations of ES complexes. In the lowest energy ES conformation, the coordination shell of MgA2+ does not include the Oδ1 atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized which includes proton transfer from the ribose O3'H3' group in ATP to Asp440 via a shuttling water molecule and PA-O3A bond cleavage and O3'-PA bond formation. The energy profile of this route is consistent with the observed reaction kinetics. In a higher energy ES conformation, MgA2+ is bound to the Oδ1(Asp440) atom as suggested in the relevant crystal structure of the protein with a substrate analog. The computed energy profile initiated by this ES is characterized by higher energy expenses to complete the reaction. Consistently with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O3'H3' group via shuttling water molecules.

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Август и Агриппа: развитие системы соправления с 29 по 18 г. до н. э.

Istoricheskii vestnik ◽

10.35549/hr.2017.2017.34958 ◽

2017 ◽

pp. 126-169

Author(s):

S.E. Tariverdieva

Keyword(s):

Political Life ◽

The Political ◽

State Administration ◽

Inheritance System ◽

The Future ◽

One Step ◽

Formal Equality ◽

Different Parts

The article deals with the development of the coregency system of Augustus and Agrippa from 29 to 18 BC: from formal and actual disparity of the coregents to their formal equality with the dominance of the princeps auctoritas. Particular attention is paid to the earlier stages of this development and to the crisis of 23 BC. The coregency system created by Augustus is often regarded by modern historians as means of ensuring uninterrupted succession of power. Agrippa as his coregent often is thought to have assumed the role of the regent who temporally replaces the princeps, just as it was in formal monarchies, or that of the tutor of the future rulers. However, the Roman system of state administration did not allow such type of regency. The princeps coregent, who was his equal in formal credentials but his inferior in terms of auctoritas, in case of the princeps death had to become the next princeps as his immediate successor. It is unlikely that later he was expected to voluntarily give up his power in favour of younger heir and to vanish from the political life altogether. The inheritance system under Augustus was like a ladder with the princeps at the top, the coregent who was also the immediate successor one step below, heirs of the next degree further down. In case of death of one of them, successors shifted one step up. The coregency had one more function: geographically it allowed Augustus and Agrippa to rule jointly the empire while staying in different parts of it.В статье исследуется развитие системы соправления Августа и Агриппы с 29 по 12 гг. до н. э.: от формального и фактического неравенства соправителей до их формального равенства при преобладании auctoritas принцепса, причём особое внимание уделяется раннему этапу этого развития и кризису 23 г. до н. э. Институт соправления, созданный Августом, часто рассматривается, как средство обеспечения бесперебойного перехода власти, причем Агриппе, как соправителю, НЕРЕДКО отводится роль регента, временно замещающего принцепса или воспитателя будущих правителей. Однако римская система государственного управления не предполагала регентства. Соправитель принцепса, равный ему по формальным полномочиям, но уступавший по auctoritas, в случае его смерти должен был СТАТЬ следующим принцепсом, ближайшим его наследником. Вряд ли предполагалось, что в будущем он должен добровольно уступить власть более молодому наследнику и исчезнуть из политической жизни. Система наследования при Августе представляла собой нечто вроде лестницы, на вершине которой стоял принцепс, на следующей ступени соправитель, он же избранный преемник, ниже наследники следующей очереди в случае смерти когото из них происходило продвижение наследников по ступеням вверх. Кроме того, соправление имело и иное значение позволяло Августу и Агриппе совместно управлять империей, находясь в разных ее частях.

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