Article
Andrology
Prafulla S. Ambulkar, Jwalant E. Waghmare, Poonam Verma Shivkumar, Pratibha Narang, Asoke K. Pal
Summary: Mutations in the SRY gene are associated with complete gonadal dysgenesis in females with 46,XY karyotype, leading to primary amenorrhea and underdeveloped secondary sexual characters. The presence of a nucleotide substitution in the HMG box domain of SRY gene was confirmed to cause 46,XY sex reversal female, affecting the nuclear transport of SRY protein and down regulation of male sex differentiation pathway.
Article
Genetics & Heredity
Bingqing Yu, Yinjie Gao, Jiangfeng Mao, Xi Wang, Min Nie, Xueyan Wu
Summary: The c.244G>T mutation in the NR5A1 gene leads to 46, XY DSD in a Chinese patient by inducing abnormal splicing of NR5A1 RNA instead of amino acid substitution of NR5A1. In silico tools predict that the variant may affect the abnormal splicing of NR5A1 RNA.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Review
Pediatrics
Silvano Bertelloni, Nina Tyutyusheva, Margherita Valiani, Franco D'Alberton, Fulvia Baldinotti, Maria Adelaide Caligo, Giampiero I. Baroncelli, Diego G. Peroni
Summary: Differences/disorders of sex development (DSD) encompass a range of congenital conditions where there is discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. Managing newborns suspected of having 46,XY DSD remains challenging, but advances in genetic testing and diagnostic methods can improve accuracy, reduce invasive procedures, and contribute to better personalized care. Society's evolving attitudes towards gender identity emphasize the importance of individualized care and quality of life for babies with 46,XY DSD.
FRONTIERS IN PEDIATRICS
(2021)
Article
Cell Biology
Yidi Wang, Yue Liu, Haotian Chen, Xiaojing Liu, Yi Zhang, Yixiang Wang, Yan Gu
Summary: In this study, FGFR2 mutation p.Cys342Arg was found to promote osteogenesis by enhancing mitochondrial metabolism-mediated FGF/FGFR-AMPK-Erk1/2 signaling pathway. This finding suggests the potential of targeting AMPK or Erk1/2 for the treatment of syndromic craniosynostosis.
Article
Pediatrics
Liwei Li, Junhong Zhang, Qing Li, Li Qiao, Pengcheng Li, Yi Cui, Shujun Li, Shirui Hao, Tongqian Wu, Lili Liu, Jianmin Yin, Pingsheng Hu, Xiaowei Dou, Shuping Li, Hui Yang
Summary: This study confirms that the compound heterozygous p.Q6X/p.H232R mutation in the SRD5A2 gene is the cause of 46,XY DSD. The p.H232R mutation reduces DHT production while attenuating the catalytic efficiency of the 5 alpha-reductase 2 enzyme.
ITALIAN JOURNAL OF PEDIATRICS
(2022)
Article
Genetics & Heredity
Brittany Croft, Anthony D. Bird, Makoto Ono, Stefanie Eggers, Stefan Bagheri-Fam, Janelle M. Ryan, Alejandra P. Reyes, Jocelyn van den Bergen, Anne Baxendale, Elizabeth M. Thompson, Andrew J. Kueh, Peter Stanton, Tim Thomas, Andrew H. Sinclair, Vincent R. Harley
Summary: 46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can cause ambiguous genitalia or complete male-to-female sex reversal. It has been found that a variant in FGF9 gene may contribute to the occurrence of GD, and other gene variants can modulate the effects of this FGF9 mutation. These findings provide important insights into the etiology of GD.
Article
Genetics & Heredity
Qi-Gen Xie, Peng Luo, Kai Xia, Zuo-Qing Li, Zhe Xu, Cheng Su, Chun-Hua Deng
Summary: 46,XY disorders of sex development (DSD) are complex genetic diseases with diverse phenotypes. Accurate genetic diagnosis is crucial for management and treatment. In this study, targeted next-generation sequencing (NGS) and whole-exome sequencing were used to investigate 74 patients with 46,XY DSD, resulting in a 37.8% diagnosis rate of pathogenic and/or likely pathogenic variants. Variants associated with steroid hormone synthesis and activation were found to be the main genetic causes of 46,XY DSD.
Article
Urology & Nephrology
Ridwan Alam, Andrew T. Gabrielson, Matthew J. Rabinowitz, Max Kates, Heather N. Di Carlo
Summary: We reported a case of a 53-year-old phenotypic female with 46,XY differences in sex development (DSD) and androgen insensitivity syndrome (AIS) who had a large intra-abdominal mass identified as localized pure seminoma within a retained gonad. Our management approach included removal of the mass and contralateral gonadectomy. This case highlights the importance of lifetime surveillance in patients with 46,XY DSD who choose to retain their gonads.
Article
Endocrinology & Metabolism
Nathalia Lisboa Gomes, Rafael Loch Batista, Mirian Y. Nishi, Antonio Marcondes Lerario, Thatiana E. Silva, Amanda de Moraes Narcizo, Anna Flavia Figueredo Benedetti, Mariana Ferreira de Assis Funari, Jose Antonio Faria Junior, Daniela Rodrigues Moraes, Lia Mesquita Lousada Quintao, Luciana Ribeiro Montenegro, Maria Teresa Martins Ferrari, Alexander A. Jorge, Ivo J. P. Arnhold, Elaine Maria Frade Costa, Sorahia Domenice, Berenice Bilharinho Mendonca
Summary: The combination of clinical/biochemical and genetic approaches significantly improves the diagnosis of 46,XY DSD, and MPS as a first-line approach helps simplify the diagnostic workflow.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Article
Obstetrics & Gynecology
Pei-Hsiu Yu, Meng-Che Tsai, Chun -Ting Chiang, Han-Yu Wang, Pao-Lin Kuo
Summary: This article reports a case of an 18-year-old phenotypically female with primary amenorrhea. The patient was found to have hypergonadotropic hypogonadism and a novel mutation in the MAP3K1 gene in the karyotype.
TAIWANESE JOURNAL OF OBSTETRICS & GYNECOLOGY
(2022)
Article
Biology
Ruoxu Chen, Steven M. Sanders, Zhiwei Ma, Justin Paschall, E. Sally Chang, Brooke M. Riscoe, Christine E. Schnitzler, Andreas D. Baxevanis, Matthew L. Nicotra
Summary: This study establishes Hydractinia as a reliable non-bilaterian model system for the study of sex determination and the evolution of sex chromosomes. By generating a linkage map and utilizing deep sequencing, the researchers found pseudoautosomal and non-recombining regions on the X and Y chromosomes of Hydractinia. They also identified genes in the non-recombining region that are specifically expressed in the male gonad. Additionally, the study observed enhanced recombination rates in the female genome and determined that Hydractinia has a haploid chromosome number of n = 15.
Article
Endocrinology & Metabolism
G. Y. Zheng, G. M. Chu, P. P. Li, R. He
Summary: This study investigated the clinical and mutational characteristics of 18 Chinese patients with 46,XY disorders of sex development (DSD). The results revealed six NR5A1 mutations, two NR0B1 mutations, six SRD5A2 mutations, and six AR mutations among the patients. Additionally, six novel genetic variants involving three genes (NR5A1, NR0B1, and AR) were identified.
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
(2023)
Article
Obstetrics & Gynecology
Arvand Akbari, Kimiya Padidar, Najmeh Salehi, Mehri Mashayekhi, Navid Almadani, Mohammad Ali Sadighi Gilani, Anu Bashambou, Ken McElreavey, Mehdi Totonchi
Summary: The rare missense variant p. S754L was found in both male and female patients with gonadal failure, indicating a potential impact on protein ATPase activity. This discovery may contribute to genetic counseling and infertility diagnosis and treatment.
HUMAN REPRODUCTION
(2021)
Article
Medicine, General & Internal
Rafael Loch Batista, Marlene Inacio, Vinicius Nahime Brito, Maria Helena Palma Sircili, Min Jeong Bag, Nathalia Lisboa Gomes, Elaine Maria Frade Costa, Sorahia Domenice, Berenice Bilharinho Mendonca
Summary: The objective of this study was to analyze aspects of sexual life and fertility desire among 46, XY DSD individuals, including those who changed their gender. The results showed that sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had long-term romantic relationships. The desire for fertility had a similar prevalence in both genders, but more women considered infertility a barrier to a long-term romantic relationship. Twelve individuals had children, mainly through adoption. Conclusion: Fertility desire was shared among 46, XY DSD individuals regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD individuals who changed from female to male gender presented similar sexual parameters as those assigned as males. Virilized genitalia at birth did not affect sexuality once surgical treatment was completed among females.
Article
Environmental Sciences
Pawel Matusik, Agnieszka Gach, Olimpia Zajdel-Cwynar, Iwona Pinkier, Grzegorz Kudela, Aneta Gawlik
Summary: A novel mutation of the CYP11A1 gene was identified in a case of congenital adrenal insufficiency with 46,XY sex reversal. The patient presented with acute adrenal crisis symptoms in the first year of life, and genetic testing revealed compound heterozygosity for a known pathogenic variant and a novel splice site mutation in the CYP11A1 gene as the likely cause of the condition.
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
(2021)
Article
Endocrinology & Metabolism
Bernat Elvira, Valerie Vandenbempt, Julia Bauza-Martinez, Raphael Crutzen, Javier Negueruela, Hazem Ibrahim, Matthew L. Winder, Manoja K. Brahma, Beata Vekeriotaite, Pieter-Jan Martens, Sumeet Pal Singh, Fernando Rossello, Pascale Lybaert, Timo Otonkoski, Conny Gysemans, Wei Wu, Esteban N. Gurzov
Summary: This study assessed the PTP protein profiles in the pancreas of type 1 diabetes patients and found that PTPN2 plays a protective role in beta-cells. Inactivation of PTPN2 in beta-cells exacerbates interferon signaling pathways and may lead to autoimmune progression.
Article
Biochemistry & Molecular Biology
Ryuichi Nakagawa, Kei Takasawa, Maki Gau, Atsumi Tsuji-Hosokawa, Hideya Kawaji, Yasuhiro Murakawa, Shuji Takada, Masashi Mikami, Satoshi Narumi, Maki Fukami, Rajini Sreenivasan, Tetsuo Maruyama, Elena J. Tucker, Liang Zhao, Josephine Bowles, Andrew Sinclair, Peter Koopman, Yoshihide Hayashizaki, Tomohiro Morio, Kenichi Kashimada
Summary: This study identified enhancers of five ovarian genes involved in early ovarian development using the expression of enhancer derived transcripts (eRNAs) as a characterization of active enhancers. Two candidate sequences for enhancers of Wnt4 and Rspo1 were identified and their enhancer activities were confirmed. Rare sequence variants were also found in these enhancer sequences in patients with impaired ovarian development. This research advances an important unmet need in forward human genetics.
HUMAN MOLECULAR GENETICS
(2022)
Article
Genetics & Heredity
Ella Thomson, Liang Zhao, Yen-Shan Chen, Enya Longmuss, Ee Ting Ng, Rajini Sreenivasan, Brittany Croft, Xin Song, Andrew Sinclair, Michael Weiss, Peter Koopman, Emanuele Pelosi
Summary: SRY is a crucial Y-chromosomal gene for male sex development in mammals. By studying the functionality of human SRY in a mouse model, we can gain deeper insights into its role in embryonic testis development. This research helps to unravel the genetic variations underlying differences and disorders in sex determination.
Article
Cardiac & Cardiovascular Systems
Monika Mohenska, Nathalia M. Tan, Alex Tokolyi, Milena B. Furtado, Mauro W. Costa, Andrew J. Perry, Jessica Hatwell-Humble, Karel van Duijvenboden, Hieu T. Nim, Yuan M. M. Ji, Natalie Charitakis, Denis Bienroth, Francesca Bolk, Celine Vivien, Anja S. Knaupp, David R. Powell, David A. Elliott, Enzo R. Porrello, Susan K. Nilsson, Gonzalo del Monte-Nieto, Nadia A. Rosenthal, Fernando J. Rossello, Jose M. Polo, Mirana Ramialison
Summary: Researchers combined transcriptomics with 3D modelling to investigate spatial gene expression in the mammalian heart by dissecting and sequencing 18 anatomical sections of the adult mouse heart. They identified known and novel genes with complex spatial expression in heart sub-compartments, and created 3D-cardiomics for easy exploration of these data in a 3D model of the heart.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Multidisciplinary Sciences
Gabriel M. Hauswirth, Victoria C. Garside, Lisa S. F. Wong, Heidi Bildsoe, Jan Manent, Yi-Cheng Chang, Christian M. Nefzger, Jaber Firas, Joseph Chen, Fernando J. Rossello, Jose M. Polo, Edwina McGlinn
Summary: Vertebral column length and shape are highly conserved within a species, but show diversity across species. This study reveals the molecular mechanisms that constrain vertebral number in mice and highlights a novel role for posterior Hox genes in this process.
NATURE COMMUNICATIONS
(2022)
Article
Developmental Biology
Liang Zhao, Ella Thomson, Ee T. Ng, Enya Longmuss, Terje Svingen, Stefan Bagheri-Fam, Alexander Quinn, Vincent R. Harley, Leonard C. Harrison, Emanuele Pelosi, Peter Koopman
Summary: Sex determination in eutherian mammals is controlled by the Y-linked gene Sry. This study focused on the gene Mmd2, which is expressed during the sex-determining period in male gonads. However, the mice deficient in Mmd2 showed normal testis development, suggesting the possible redundancy of PAQR factors in gonadal development. These findings shed light on the challenges in identifying genes involved in sex determination and may help explain the limited genes associated with disorders/differences of sex development in humans.
SEXUAL DEVELOPMENT
(2023)
Article
Multidisciplinary Sciences
Hue M. La, Jinyue Liao, Julien M. D. Legrand, Fernando J. Rossello, Ai-Leen Chan, Vijesh Vaghjiani, Jason E. Cain, Antonella Papa, Tin Lap Lee, Robin M. Hobbs
Summary: This study uncovers the roles of growth factor signalling and mTORC1 in the regeneration of spermatogonial stem cells (SSCs). Single-cell analysis reveals the unique molecular features of regenerative SSCs and the changes in the composition of undifferentiated spermatogonia during germline recovery. The data suggest that transient mTORC1 activation is critical for the regenerative response, while sustained mTORC1 signalling is detrimental for SSC maintenance. Inhibition of growth factor signalling disrupts the regenerative state and limits germline recovery.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. de Weerd, Jens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, Ricky W. Johnstone
Summary: Inhibition of HDACs can induce differentiation and therapeutic effects in AML cells, and epigenetic rewiring of pDCs enhances antitumor immunity, offering a new therapeutic approach.
Article
Chemistry, Multidisciplinary
Andrew M. K. Law, Jiamin Chen, Yolanda Colino-Sanguino, Laura Rodriguez de la Fuente, Guocheng Fang, Susan M. Grimes, Hongxu Lu, Robert J. Huang, Sarah T. Boyle, Jeron Venhuizen, Lesley Castillo, Javad Tavakoli, Joanna N. Skhinas, Ewan K. A. Millar, Julia Beretov, Fernando J. Rossello, Joanne L. Tipper, Christopher J. Ormandy, Michael S. Samuel, Thomas R. Cox, Luciano Martelotto, Dayong Jin, Fatima Valdes-Mora, Hanlee P. Ji, David Gallego-Ortega
Summary: ALTEN is a biomimetic tissue platform that enables ex vivo analysis of tissue biopsies while preserving the original cellular milieu. Its use of single-cell genomics allows for rapid and accurate analysis of cellular responses to perturbations.
Article
Cell & Tissue Engineering
Christian M. Nefzger, Thierry Jarde, Akanksha Srivastava, Jan Schroeder, Fernando J. Rossello, Katja Horvay, Mirsada Prasko, Jacob M. Paynter, Joseph Chen, Chen-Fang Weng, Yu B. Y. Sun, Xiaodong Liu, Eva Chan, Nikita Deshpande, Xiaoli Chen, Y. Jinhua Li, Jahnvi Pflueger, Rebekah M. Engel, Anja S. Knaupp, Kirill Tsyganov, Susan K. Nilsson, Ryan Lister, Owen J. L. Rackham, Helen E. Abud, Jose M. Polo
Summary: The impact of aging on intestinal stem cells is not fully understood. This study identified widespread epigenetic and transcriptional alterations in old ISCs. Key transcription factors were identified that drive molecular and functional differences between old and young states. These findings contribute to enhancing the regenerative capacity of intestinal stem cells.
NPJ REGENERATIVE MEDICINE
(2022)
Article
Genetics & Heredity
Brittany Croft, Anthony D. Bird, Makoto Ono, Stefanie Eggers, Stefan Bagheri-Fam, Janelle M. Ryan, Alejandra P. Reyes, Jocelyn van den Bergen, Anne Baxendale, Elizabeth M. Thompson, Andrew J. Kueh, Peter Stanton, Tim Thomas, Andrew H. Sinclair, Vincent R. Harley
Summary: 46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can cause ambiguous genitalia or complete male-to-female sex reversal. It has been found that a variant in FGF9 gene may contribute to the occurrence of GD, and other gene variants can modulate the effects of this FGF9 mutation. These findings provide important insights into the etiology of GD.
Correction
Multidisciplinary Sciences
Magnus Zethoven, Luciano Martelotto, Andrew Pattison, Blake Bowen, Shiva Balachander, Aidan Flynn, Fernando J. Rossello, Annette Hogg, Julie A. Miller, Zdenek Frysak, Sean Grimmond, Lauren Fishbein, Arthur S. Tischler, Anthony J. Gill, Rodney J. Hicks, Patricia L. M. Dahia, Roderick Clifton-Bligh, Karel Pacak, Richard W. Tothill
NATURE COMMUNICATIONS
(2023)
Review
Urology & Nephrology
Alejandra P. Reyes, Nayla Y. Leon, Emily R. Frost, Vincent R. Harley
Summary: In this review, the authors provide an overview of the embryology and genetics of typical sex development and discuss the clinical manifestations and genetic causes of differences in sex development. Sex development relies on gene networks and hormonal factors, and differences in sex development (DSD) can arise from congenital alterations during these processes. Understanding the genetics and embryology of sex development is essential for diagnosing and managing DSD, and advances have been made in understanding the genetic causes of DSD, especially for 46,XY DSD. Further research is needed to better understand 46,XX DSD and identify additional genetic causes.
NATURE REVIEWS UROLOGY
(2023)
Article
Endocrinology & Metabolism
Anthony D. Bird, Emily R. Frost, Stefan Bagheri-Fam, Brittany M. Croft, Janelle M. Ryan, Liang Zhao, Peter Koopman, Vincent R. Harley
Summary: During sex determination in mice, FGFR2c is involved in testis development while FOXL2 and WNT4/RSPO1 pathways drive ovarian development. The role of FGFR2 in the ovary and its requirement in the testis after sex determination are not clear.