scholarly journals MAMLD1 and Differences/Disorders of Sex Development: An Update

2021 ◽  
pp. 1-12
Author(s):  
Mami Miyado ◽  
Maki Fukami ◽  
Tsutomu Ogata
Keyword(s):  
Leydig Cell ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Gene Interactions ◽  
Testicular Function ◽  
Ovarian Dysfunction ◽  
Causative Gene ◽  
Fetal Testis ◽  
Sex Development ◽  
Age Dependent

<i>MAMLD1</i> (alias <i>CXorf6</i>) was first documented in 2006 as a causative gene of 46,XY differences/disorders of sex development (DSD). <i>MAMLD1</i>/<i>Mamld1</i> is expressed in the fetal testis and is predicted to enhance the expression of several Leydig cell-specific genes. To date, hemizygous <i>MAMLD1</i> variants have been identified in multiple 46,XY individuals with hypomasculinized external genitalia. Pathogenic <i>MAMLD1</i> variants are likely to cause genital abnormalities at birth and are possibly associated with age-dependent deterioration of testicular function. In addition, some <i>MAMLD1</i> variants have been identified in 46,XX individuals with ovarian dysfunction. However, recent studies have raised the possibility that <i>MAMLD1</i> variants cause 46,XY DSD and ovarian dysfunction as oligogenic disorders. Unsolved issues regarding MAMLD1 include the association between <i>MAMLD1</i> variants and 46,XX testicular DSD, gene-gene interactions in the development of <i>MAMLD1</i>-mediated DSD, and intracellular functions of MAMLD1.

MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration

2019 ◽  
Vol 28 (14) ◽  
pp. 2319-2329 ◽  
Author(s):  
Kohei Hamanaka ◽  
Atsushi Takata ◽  
Yuri Uchiyama ◽  
Satoko Miyatake ◽  
Noriko Miyake ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
De Novo ◽  
Clinical Symptoms ◽  
Disorders Of Sex Development ◽  
Sequencing Data ◽  
Causative Gene ◽  
Sex Development ◽  
And Migration ◽  
Proliferation And Migration

AbstractDisorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case–control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Müllerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.

scholarly journals Characterising SRD5A2 Gene Variants in 37 Indonesian Patients with 5-Alpha-Reductase Type 2 Deficiency

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Nanis S. Marzuki ◽  
Firman P. Idris ◽  
Hannie D. Kartapradja ◽  
Alida R. Harahap ◽  
Jose R. L. Batubara
Keyword(s):  
Autosomal Recessive ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Compound Heterozygous ◽  
Phenotypic Characteristics ◽  
Sex Development ◽  
Srd5a2 Gene ◽  
Diagnostic Approaches ◽  
Autosomal Recessive Condition

The 5-alpha-reductase type 2 deficiency (5ARD2) is an autosomal recessive condition associated with impairment in the conversion of testosterone to dihydrotestosterone. This condition leads to undervirilisation in 46,XY individuals. To date, there have been more than 100 variations identified in the gene responsible for 5ARD2 development (steroid 5-alpha-reductase 2, SRD5A2). However, few studies have examined the molecular characterisation of Indonesian 5ARD2 cases. In the current study, we analysed 37 subjects diagnosed with 46,XY DSD (disorders of sex development) with confirmed variations in the SRD5A2 gene. We examined results from testosterone/dihydrotestosterone (T/DHT) and urinary etiocholanolone/androsterone (Et/An) ratios, as well as from molecular and clinical analyses. Twelve variants in the SRD5A2 gene were identified, and 6 of which were novel, namely, c.34–38delGinsCCAGC, p.Arg50His, p.Tyr136∗, p.Gly191Arg, p.Phe194Ile, and p.Ile253Val variants. Moreover, we determined that 20 individuals contained harmful mutations, while the remaining 17 variants were benign. Those containing harmful mutations exhibited more severe phenotypes with median external genitalia masculinisation scores (EMS) of 3 (1.5–9) and were more likely to be diagnosed at a later age, reared as female, and virilised at pubertal age. In addition, the respective sensitivities for detecting severe 5ARD2 cases using T/DHT (cutoff: 10) and urinary Et/An ratios (cutoff: 0.95) were 85% and 90%, whereas mild cases were only identified with 64.7% and 47.1% sensitivity, respectively. Although we were unable to identify clear correlations between genotypic and phenotypic characteristics in this study, we clearly showed that individuals who were homozygous or compound heterozygous for any of the harmful mutations were more likely to exhibit classic 5ARD2 phenotypes, lower EMS, female assignment at birth, and virilisation during puberty. These results serve to inform the development of improved clinical and molecular 5ARD2 diagnostic approaches, specifically in Indonesian patients.

scholarly journals Comprehensive Transcriptome Analysis of Hypothalamus Reveals Genes Associated With Disorders of Sex Development in Pigs

2020 ◽  
Author(s):  
Shuwen Tan ◽  
Yi Zhou ◽  
Haiquan Zhao ◽  
Jinhua Wu ◽  
Hui Yu ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Rna Isolation ◽  
Functional Enrichment ◽  
Regulation Mechanism ◽  
Normal Female ◽  
Sex Development ◽  
Mirna Expression Profiles ◽  
Hormone Biosynthesis

Abstract Background Disorders of sex development (DSD) is a chronic autoimmune disease characterized by systemic inflammation, pathological osteogenesis, and endocrine abnormality. However, its genetic etiology remains mostly unknown. In addition, little research focuses on the regulation mechanism from the view of transcriptomics in the hypothalamic-pituitary-gonadal axis (HPGA). The hypothalamus is the integrated center of the HPGA mediating neural, hormonal, and environmental stimulus to sex development. Methods Three XX-DSD (SRY-negative) pig (DSD) and three NF pigs (five months old, 40 kg ± 5 kg) were selected by external genitalia observation and sex determining region Y gene (SRY) detection. The hypothalamus were sampled for RNA isolation, and the mRNA, lncRNA and miRNA expression profiles were analyzed by sequencing. Results A total of 1,258 lncRNAs, 1,086 mRNAs, and 61 microRNAs were found to differentially express in XX-DSD pigs compared with normal female pigs. Many genes in hormone biosynthesis and secretion pathway are significantly up-regulated, and the up-regulation of GNRH1, KISS1 and AVP may be the candidate genes leading the abnormal secretion of GnRH. Next, we predicted the lncRNA-miRNA-mRNA co-expression triplets and constructed three competing endogenous RNA (ceRNA) potentially associated with DSD. Functional enrichment suggested TCONS_00340886, TCONS_00000204 and miR-181a were related to GnRH secretion. Conclusions Our research revealed the first transcriptomic profile in the hypothalamus of XX-DSD pigs and provided new insight in coding and non-coding RNAs that may be associated with DSD in pigs.

scholarly journals Leydig Cell Tumor in a Patient with 46,XX Disorder of Sex Development (DSD), Ovotesticular: A Case Report and a Review of the Literature

2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Steffen Gretser ◽  
Maria-Noemi Welte ◽  
Frederik Roos ◽  
Jens Köllermann
Keyword(s):  
Leydig Cell ◽  
External Genitalia ◽  
Rare Condition ◽  
Leydig Cell Tumor ◽  
Cell Tumor ◽  
Mri Scan ◽  
Disorder Of Sex Development ◽  
Left Testicle ◽  
Sex Development ◽  
Atypical Development

Disorder of sex development (DSD) is a rare condition with atypical development of chromosomal, gonadal, or anatomical sex. It is classified in different subgroups based on the patient’s karyotype, gonadal dysgenesis, and the appearance of the internal and external genitalia. Within the subgroups, the risk for developing neoplasms varies a lot. Here, we report the case of a 41-year-old patient with disorder of sex development, showing a 46,XX karyotype with an ovotestis and the simultaneous manifestation of a Leydig cell tumor in the ovotestis. The patient initially presented with infertility, and a suspicious lesion of the left testicle was noted on MRI-Scan. Upon resection, a Leydig cell tumor and an ovotestis were diagnosed. Nongerm call tumors are rare in patients with DSD. We report a nongerm cell tumor in a patient with 46,XX DSD, ovotesticular. This shows that although 46,XX DSD, ovotesticular is known to have a low potential for germ cell neoplasia, nongerm cell tumors can develop and should be into account for the management of those patients.

scholarly journals Clinical and molecular spectrum of 46, XY disorders of sex development that harbour MAMLD1 variations: Case series and review of literature

2020 ◽  
Author(s):  
Li Lele ◽  
Lijun Fan ◽  
Fenqi Gao ◽  
Di Wu ◽  
Chunxiu Gong
Keyword(s):  
Protein Function ◽  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Case Series ◽  
In Silico Analysis ◽  
Causative Role ◽  
Causative Gene ◽  
Sex Development ◽  
Clinical Series

Abstract Background Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46, XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46, XY DSD. Cases of 46, XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.Results Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.A356X, p.G152X, and p.G124X) and six missense (p.P334S, p.S662A, p.A421P,p.T992I, p.P542S, and p.A927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662A, and p.A927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.Conclusion Patients with 46, XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46, XY DSD.

scholarly journals AMH and AMHR2 Involvement in Congenital Disorders of Sex Development

2021 ◽  
pp. 1-9
Author(s):  
Franco G. Brunello ◽  
Rodolfo A. Rey
Keyword(s):  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Fetal Life ◽  
Fallopian Tubes ◽  
Female Fetus ◽  
Sequencing Technologies ◽  
Sex Development ◽  
Mullerian Ducts ◽  
Gene Maps

Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina. The human <i>AMH</i> gene maps to 19p13.3 and consists of 5 exons and 4 introns spanning 2,764 bp. The <i>AMHR2</i> gene maps to 12q13.13, consists of 11 exons, and is 7,817 bp long. Defects in the AMH pathway are the underlying etiology of a subgroup of disorders of sex development (DSD) in 46,XY patients. The condition is known as the persistent müllerian duct syndrome (PMDS), characterized by the existence of a uterus and fallopian tubes in a boy with normally virilized external genitalia. Approximately 200 cases of patients with PMDS have been reported to date with clinical, biochemical, and molecular genetic characterization. An updated review is provided in this paper. With highly sensitive techniques, AMH and AMHR2 expression has also been detected in other tissues, and massive sequencing technologies have unveiled variants in <i>AMH</i> and <i>AMHR2</i> genes in hitherto unsuspected conditions.

Molecular Characteristics of Sequence Variants in GATA4 in Patients with 46,XY Disorders of Sex Development without Cardiac Defects

2019 ◽  
Vol 13 (5-6) ◽  
pp. 240-245
Author(s):  
Jin-Ho Choi ◽  
Yena Lee ◽  
Arum Oh ◽  
Gu-Hwan Kim ◽  
Han-Wook Yoo
Keyword(s):  
Heart Defects ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Pathogenic Mutation ◽  
Luciferase Reporter ◽  
Molecular Characteristics ◽  
Sequence Variants ◽  
Sex Development ◽  
Stimulation Tests

A <i>GATA4</i> haploinsufficiency has been well described in patients with congenital heart defects (CHDs), whilst only a few studies have reported mutations related to a 46,XY disorder of sex development (DSD) phenotype. This study investigated the clinical phenotypes and molecular characteristics of two 46,XY DSD patients harboring <i>GATA4</i> variants. Mutation analysis was performed using a targeted gene panel or whole-exome sequencing. The transactivation activity of each variant protein was examined by in vitro luciferase reporter assay using the <i>AMH</i> and <i>SRY</i> promoters. Subject 1 presented with a micropenis and hypospadias. Subject 2 showed complete female external genitalia with a 46,XY karyotype. Both patients were responsive to hCG stimulation tests and did not manifest CHD. A novel heterozygous variant, c.643A>G (p.R215G), in <i>GATA4</i> was identified in Subject 1, whereas Subject 2 harbored a previously reported variant, c.1220C>A (p.P407Q), in <i>GATA4</i> and a previously known pathogenic mutation, i.e., c.226C>T (p.Q76*) in the <i>AR</i> gene. The reporter assays using the <i>SRY</i> and <i>AMH</i> promoters revealed decreased transcriptional activity of both p.P407Q and p.R215G. However, the <i>GATA4</i> p.P407Q variant was classified as likely benign. In conclusion, it is essential to integrate clinical features and endocrine findings when interpreting sequence variants.

scholarly journals Disorders of Sex Development: Can You Be Sure This Baby Is A Boy or Girl? We Must See Beyond The Diagnosis

2019 ◽  
Vol 10 (2) ◽  
pp. 103-110
Author(s):  
Mohammed Shadrul Alam ◽  
Mirza Kamrul Zahid ◽  
Paritosh Kumar Palit ◽  
Abhi Kumar Chakraborty ◽  
Nirupama Saha ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Sex Development ◽  
Newborn Children

Throughout the pregnancy, the parents have anticipated whether their child will be a boy or a girl. No part of a newborn baby’s anatomy arouses as much interest initially as the external genitalia. Most newborn children have the typical features of a boy or girl, but in some cases the baby’s sex can’t be clearly identified. Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex.1 Disorders of sex development (DSDs), formerly termed intersex conditions, are congenital conditions in which development of the chromosomal, gonadal, or anatomic sex is atypical and may affect up to 1:1000 individuals in the population.2 J Shaheed Suhrawardy Med Coll, December 2018, Vol.10(2); 103-110

scholarly journals Genetic Analysis for the Diagnosis of Disorders of Sexual Development in Indonesia

2016 ◽  
Vol 2 (2) ◽  
pp. 44
Author(s):  
Sultana MH Faradz
Keyword(s):  
Sexual Development ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Gonadal Development ◽  
Androgen Insensitivity Syndrome ◽  
Medical Professionals ◽  
Adrenal Hyperplasia ◽  
Disorders Of Sexual Development ◽  
Sex Development

Disorders of sex development (DSD) is defined by congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical, while in clinical practice this term means any abnormality of the external genitalia. DSD patients have been managed by a multidisciplinary gender team in our center as collaboration between Dr. Kariadi province referral hospital and Faculty of Medicine Diponegoro University. Diagnosis should be established by specific physical examination hormonal, chromosomal and DNA studies; and imaging for most of the cases depending on indication.Since 2004 the involvement of molecular and cytogenetic analysis so far can diagnosed many of the DSD cases. Most of the genetically proven cases were Congenital Adrenal hyperplasia, Androgen Insensitivity syndrome and sex chromosomal DSD that lead abnormal gonadal development.  Many of them remain undiagnosed, further testing such as advanced DNA study should be carried out in collaboration with other center in overseas.The novel genes were found in some cases that contributed for the management of DSD.  Information for medical professionals, patients, family members and community about the availability and necessity of DSD diagnosis should be delivered to improve DSD management and patient quality of life.

scholarly journals Clinical and molecular spectrum of 46, XY disorders of sex development that harbour MAMLD1 variations: Case series and review of literature

2020 ◽  
Author(s):  
Li Lele ◽  
Lijun Fan ◽  
Fenqi Gao ◽  
Di Wu ◽  
Chunxiu Gong
Keyword(s):  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Case Series ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Causative Role ◽  
Causative Gene ◽  
Sex Development ◽  
Clinical Series

Abstract Background Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46, XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46, XY DSD. Cases of 46, XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10)or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.Results Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropeniswere observedfor the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.A356X, p.G152X, and p.G124X) and six missense (p.P334S, p.S662A, p.A421P,p.T992I, p.P542S, and p.A927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662A, and p.A927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.Conclusion Patients with 46, XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46, XY DSD.

Sign in / Sign up

Export Citation Format

Share Document