MONICA MALHEIROS FRANCA
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
6 resultados
Resultados de Busca
Agora exibindo 1 - 6 de 6
- Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency(2019) FRANCA, Monica M.; NISHI, Mirian Y.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; BARACAT, Edmund C.; HAYASHIDA, Sylvia A. Y.; MACIEL, Gustavo A. R.; JORGE, Alexander A. L.; MENDONCA, Berenice B.Background/Aim: Primary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient. Patient and methods: An adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelect(xT) DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing. Results: Two rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants. Conclusion: Our results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.
conferenceObject Whole-Exome Sequencing Reveals RAD51B Variant in Two Sisters with Primary Ovarian Failure(2016) FRANCA, Monica; FUNARI, Mariana; NISHI, Mirian; DOMENICE, Sorahia; LATRONICO, Ana Claudia; JORGE, Alexander; LERARIO, Antonio; MENDONCA, Berenice- Exome Sequencing Reveals the POLR3H Gene as a Novel Cause of Primary Ovarian Insufficiency(2019) FRANCA, Monica M.; HAN, Xingfa; FUNARI, Mariana F. A.; LERARIO, Antonio M.; NISHI, Mirian Y.; FONTENELE, Eveline G. P.; DOMENICE, Sorahia; JORGE, Alexander A. L.; GARCIA-GALIANO, David; ELIAS, Carol F.; MENDONCA, Berenice B.Context: Primary ovarian insufficiency (POI) is a cause of female infertility. However, the genetic etiology of this disorder remains unknown in most patients with POI. Objective: To investigate the genetic etiology of idiopathic POI. Patients and Methods: We performed whole-exome sequencing of 11 families with idiopathic POI. To gain insights into the potential mechanisms associated with this mutation, we generated two mouse lines via clustered regularly interspaced short palindromic repeats/Cas9 technology. Results: A pathogenic homozygous missense mutation (c.149A>G; p.Asp50G ly) in the POLR3H gene in two unrelated families was identified. Pathogenic mutations in this subunit have not been associated with human disorders. Loss-of-function Polr3h mutation in mice caused early embryonic lethality. Mice with homozygous point mutation (Polr3h(D50G)) were viable but showed delayed pubertal development, characterized by late first estrus or preputial separation. The Polr3h(D50G) female and male mice showed decreased fertility later in life, associated with small litter size and increased time to pregnancy or to impregnate a female. Polr3h(D50G) mice displayed decreased expression of ovarian Foxo3a and lower numbers of primary follicles. Conclusion: Our manuscript provides a case of POI caused by missense mutation in POLR3H, expanding the knowledge of molecular pathways of the ovarian function and human infertility. Screening of the POLR3H gene may elucidate POI cases without previously identified genetic causes, supporting approaches of genetic counseling.
- Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region (vol 107, pg 127, 2018)(2018) MACEDO, D. B.; FRANCA, M. M.; MONTENEGRO, L. R.; CUNHA-SILVA, M.; BESSA, D. S.; ABREU, A. P.; KAISER, U. B.; MENDONCA, B. B.; JORGE, A. A. L.; BRITO, V. N.; LATRONICO, A. N.
conferenceObject Isolated Growth Hormone Deficiency with Advanced Bone Age: Phenotypic Interaction between GHRH Receptor and CYP21A2 Mutations Diagnosed by Sanger and Whole Exome Sequencing(2016) CORREA, F. A.; FRANCA, M. M.; FANG, Q.; MA, Q.; OZEL, B. A.; BACHEGA, T. A.; RODRIGUES, A.; LI, J. Z.; MENDONCA, B. B.; JORGE, A. A. L.; CARVALHO, L. R.; CAMPER, S. A.; ARNHOLD, I. J. P.- Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region(2018) MACEDO, Delanie B.; FRANCA, Monica M.; MONTENEGRO, Luciana R.; CUNHA-SILVA, Marina; BESSA, Danielle S.; ABREU, Ana Paula; KAISER, Ursula B.; MENDONCA, Berenice B.; JORGE, Alexander A. L.; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaContext: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. Patients/Methods: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5'-regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1-7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. Results: We identified a rare heterozygous 4-nt deletion (c.-150_-147delTCAG; -38 to -41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream responsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150_-147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. Conclusion: A rare genetic alteration in the regulatory region of MKRN3 causes CPP. (c) 2018 S. Karger AG, Basel