RESUMO
The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5' regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.
Assuntos
Disgenesia Gonadal , Testículo , Animais , Feminino , Humanos , Masculino , Linhagem Celular , Mamíferos/genética , Sequências Reguladoras de Ácido Nucleico , Células de Sertoli/metabolismo , Proteína da Região Y Determinante do Sexo/genética , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Testículo/metabolismoRESUMO
This is a case report of a neonate who was antenatally diagnosed with jejunal atresia which turned out to be duodenal atresia with apple peel syndrome. A previous sibling, who also had apple peel but with jejunal atresia, succumbed to sepsis after surgery. The first sibling had jejunal stenosis and had died of sepsis following surgery. Combination of duodenal atresia with apple peel is extremely rare. This coupled with a familial condition is rarer still. This case was challenging due to the short length of the gut and prolonged need for total parenteral nutrition and sepsis in postoperative period.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/métodos , Obstrução Duodenal , Atresia Intestinal , Jejunostomia/métodos , Sepse Neonatal , Adulto , Diagnóstico Diferencial , Obstrução Duodenal/diagnóstico , Obstrução Duodenal/etiologia , Obstrução Duodenal/fisiopatologia , Obstrução Duodenal/cirurgia , Duodeno/anormalidades , Duodeno/diagnóstico por imagem , Duodeno/cirurgia , Feminino , Humanos , Recém-Nascido , Atresia Intestinal/diagnóstico , Atresia Intestinal/genética , Atresia Intestinal/fisiopatologia , Atresia Intestinal/cirurgia , Jejuno/anormalidades , Jejuno/diagnóstico por imagem , Jejuno/cirurgia , Anamnese , Sepse Neonatal/diagnóstico , Sepse Neonatal/etiologia , Sepse Neonatal/terapia , Nutrição Parenteral Total/métodos , Gravidez , Diagnóstico Pré-Natal/métodos , Doenças Raras/diagnóstico , Irmãos , Resultado do TratamentoRESUMO
This paper describes a rare case of a seven-month-old infant with right-sided congenital diaphragmatic hernia, who was found to have fusion of his herniated part of liver with lower lobe of right lung. The report describes clinical presentation and successful surgical management along with a review of the world literature.