MIRIAN YUMIE NISHI
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
18 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 18
- Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery(2019) CORREA, Fernanda A.; NAKAGUMA, Marilena; MADEIRA, Joao L. O.; NISHI, Mirian Y.; ABRAO, Milena G.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clinicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe.
- Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing(2019) HOMMA, Thais Kataoka; FREIRE, Bruna Lucheze; KAWAHIRA, Rachel Sayuri Honjo; DAUBER, Andrew; FUNARI, Mariana Ferreira de Assis; LERARIO, Antonio Marcondes; NISHI, Mirian Yumie; ALBUQUERQUE, Edoarda Vasco de; VASQUES, Gabriela de Andrade; COLLETT-SOLBERG, Paulo Ferrez; SUGAYAMA, Sofia Mizuho Miura; BERTOLA, Debora Romeo; KIM, Chong Ae; ARNHOLD, Ivo Jorge Prado; MALAQUIAS, Alexsandra Christianne; JORGE, Alexander Augusto de LimaObjective To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. Study design For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology. Results Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair. Conclusions The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.
- Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum(2021) NAKAGUMA, Marilena; FERREIRA, Nathalia Garcia Bianchi Pereira; BENEDETTI, Anna Flavia Figueredo; MADI, Mariana Cotarelli; SILVA, Juliana Moreira; LI, Jun Z.; MA, Qianyi; OZEL, Ayse Bilge; FANG, Qing; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; MONTENEGRO, Luciana Ribeiro; FUNARI, Mariana Ferreira de Assis; NISHI, Mirian Yumie; ARNHOLD, Ivo Jorge Prado; JORGE, Alexander Augusto de Lima; MENDONCA, Berenice Bilharinho de; CAMPER, Sally Ann; CARVALHO, Luciani R.We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (Delta Delta G = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.
- Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature(2013) VASQUES, Gabriela A.; AMANO, Naoko; DOCKO, Ana J.; FUNARI, Mariana F. A.; QUEDAS, Elisangela P. S.; NISHI, Mirian Y.; ARNHOLD, Ivo J. P.; HASEGAWA, Tomonobu; JORGE, Alexander A. L.Context: Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for mutations in natriuretic peptide receptor B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some children with idiopathic short stature (ISS). Objective: The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS. Patients and Methods: The NPR2 coding region was directly sequenced in 47 independent patients with ISS. The functional consequences of NPR2 nonsynonymous variations were established using in vitro cell-based assays. Results: Three novel heterozygous NPR2 mutations were identified: c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), and c.2455C>T (p.Arg819Cys). These allelic variants were not found in our controls or in the 1000 Genomes database. In silico analysis suggested that the three missense mutations are probably damaging. All of them were selected for in vitro functional evaluation. Cells transfected with the three mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide. Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect. These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7). One of these patients and two relatives have disproportionate short stature, whereas in another patient a nonspecific skeletal abnormality was observed. All three of these patients were treated with recombinant human GH (33-50 mu g/kg.d) without significant height SD score change during therapy. Conclusions: We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature.
- Autosomal recessive form of isolated growth hormone deficiency is more frequent than the autosomal dominant form in a Brazilian cohort(2014) LIDO, Andria C. V.; FRANCA, Marcela M.; CORREA, Fernanda A.; OTTO, Aline P.; CARVALHO, Luciani R.; QUEDAS, Elisangela P. S.; NISHI, Mirian Y.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Background: In most studies, the autosomal dominant (type II) form of isolated growth hormone deficiency (IGHD) has been more frequent than the autosomal recessive (type I) form. Our aim was to assess defects in the GH1 in short Brazilian children with different GH secretion status. Subjects and methods: We selected 135 children with postnatal short stature and classified according to the highest GH peak at stimulation tests in: severe IGHD (peak GH <= 3.3 mu g/L, n = 38, all with normal pituitary magnetic resonance imaging); GH peak between 3.3 and 10 mu g/L (n = 76); and GH peak >10 mu g/L (n = 21). The entire coding region of GH1 was sequenced and complete GH1 deletions were assessed by Multiplex Ligation Dependent Probe Amplification and restriction enzyme digestion. Results: Patients with severe IGHD had a higher frequency of consanguinity, were shorter, had lower levels of IGF-1 and IGFBP-3, and despite treatment with lower GH doses had a greater growth response than patients with GH peak >= 3.3 mu g/L. Mutations were found only in patients with severe IGHD (GH peak <3.3 mu g/L). Eight patients had autosomal recessive IGHD: Seven patients were homozygous for GH1 deletions and one patient was compound heterozygous for a GH1 deletion and the novel c.171 + 5G>C point mutation in intron 2, predicted to abolish the donor splice site. Only one patient, who was heterozygous for the c.291 + 1G>T mutation located at the universal donor splice site of intron 3 and predicts exon 3 skipping, had an autosomal dominant form. Conclusion: Analysis of GH1 in a cohort of Brazilian patients revealed that the autosomal recessive form of IGHD was more common than the dominant one, and both were found only in severe IGHD.
- FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies(2015) CORREA, Fernanda A.; TRARBACH, Ericka B.; TUSSET, Cintia; LATRONICO, Ana Claudia; MONTENEGRO, Luciana R.; CARVALHO, Luciani R.; FRANCA, Marcela M.; OTTO, Aline P.; COSTALONGA, Everlayny F.; BRITO, Vinicius N.; ABREU, Ana Paula; NISHI, Mirian Y.; JORGE, Alexander A. L.; ARNHOLD, Ivo J. P.; SIDIS, Yisrael; PITTELOUD, Nelly; MENDONCA, Berenice B.The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p. Arg85Cys and p. Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca2+ pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.
- Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17 alpha-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients(2017) FERNANDEZ-CANCIO, Monica; GARCIA-GARCIA, Emilio; GONZALEZ-CEJUDO, Carmen; MARTINEZ-MAESTRE, Maria-Angeles; MANGAS-CRUZ, Miguel-Angel; GUERRA-JUNIOR, Gil; MELLO, Maricilda Pandi de; ARNHOLD, Ivo J. P.; NISHI, Mirian Y.; MENDONCA, Berenice Bilharinho; GARCIA-ARUMI, Elena; AUDI, Laura; TIZZANO, Eduardo; CARRASCOSA, Antonio17 alpha-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46, XY and 46, XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonad-otropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46, XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy. (C) 2017 S.Karger AG, Basel
- GH-Releasing Hormone Receptor Gene: A Novel Splice-Disrupting Mutation and Study of Founder Effects(2012) MARUI, Suemi; TRARBACH, Ericka B.; BOGUSZEWSKI, Margaret C. S.; FRANCA, Marcela M.; JORGE, Alexander A. L.; INOUE, Hiroshi; NISHI, Mirian Y.; LACERDA FILHO, Luiz de; AGUIAR-OLIVEIRA, Manuel H.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.Background: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). Objective: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. Methods: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c. 1146G>A (p.E382E) mutation. Results: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. Conclusion: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.
- Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver-Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11(2012) MONTENEGRO, Luciana R.; LEAL, Andrea C.; COUTINHO, Debora C.; VALASSI, Helena P. L.; NISHI, Mirian Y.; PARNHOLD, Ivo J.; MENDONCA, Berenice B.; JORGE, Alexander A. L.Background: Hypomethylation of the paternal imprinting center region 1 (ICR1) is the most frequent molecular cause of Silver-Russell syndrome (SRS). Clinical evidence suggests that patients with this epimutation have mild IGF1 insensitivity. Objective: To assess in vitro IGF1 action in fibroblast culture from a patient with SRS and IGF1 insensitivity. Methods: Fibroblast cultures from one patient with SRS due to ICR1 demethylation and controls were established. The SRS patient has severe growth failure, elevated IGF1 level, and poor growth rate during human recombinant GH treatment. IGF1 action was assessed by cell proliferation, AKT, and p42/44-MAPK phosphorylation. Gene expression was determined by real-time PCR. Results: Despite normal IGF1R sequence and expression, fibroblast proliferation induced by IGF1 was 50% lower in SRS fibroblasts in comparison with controls. IGF1 and insulin promoted a p42/44-MAPK activation in SRS fibroblasts 40 and 36%, respectively, lower than that in control fibroblasts. On the other hand, p42/44-MAPK activation induced by EGF stimulation was only slightly reduced (75% in SRS fibroblasts in comparison with control), suggesting a general impairment in MAPK pathway with a greater impairment of the stimulation induced by insulin and IGF1 than by EGF. A PCR array analysis disclosed a defect in MAPK pathway characterized by an increase in DUSP4 and MEF2C gene expressions in patient fibroblasts. Conclusion: A post-receptor IGF1 insensitivity was characterized in one patient with SRS and ICR1 hypomethylation. Although based on one unique severely affected patient, these results raise an intriguing mechanism to explain the postnatal growth impairment observed in SRS patients that needs confirmation in larger cohorts.
conferenceObject RAB3IP and DGCR8 as a Potentially Pathogenic Novel Candidate Gene Involving in Growth Disorders(2016) HOMMA, Thais; FUNARI, Mariana; LERARIO, Antonio; FREIRE, Bruna; NISHI, Mirian; YAMAMOTO, Guilherme; NASLAVSKY, Michel; ZATZ, Mayana; ARNHOLD, Ivo; JORGE, Alexander