MARCELA MOURA FRANCA
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- 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.
- 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.
- Clarification of intellectual abilities in patients with GLI2 mutations cited by kevelam et al., 2012 Am J med genet part A(2012) FRANCA, Marcela M.; ARNHOLD, Ivo J. P.
bookPart Deficiência isolada de GH por deleção no gene GH1(2012) FRANçA, Marcela M.; OLIVEIRA, Suely B. de; COSTALONGA, Everlayny Fiorot; ARNHOLD, Ivo Jorge Prado- Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly(2013) FRANCA, Marcela M.; JORGE, Alexander A. L.; CARVALHO, Luciani R. S.; COSTALONGA, Everlayny F.; OTTO, Aline P.; CORREA, Fernanda A.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.Objective GLI2 is a downstream transcription factor in Sonic Hedgehog signalling, acting early in ventral forebrain and pituitary development. Heterozygous nonsense GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD), with or without holoprosencephaly. The aim of this study was to screen for GLI2 mutations in a large cohort of patients with congenital GH deficiency. Design and Patients The GLI2 coding region of 41 patients with severe isolated GH deficiency (IGHD) and 136 patients with CPHD was amplified by PCR using intronic primers and sequenced. The frequency of GLI2 variants was verified in up to 155 Brazilian controls and in the 1000 Genomes database. The consequences of allelic variants were analysed by the Polyphen, SIFT, Mutationtaster and SNAP prediction sites. Results Eighteen different heterozygous non-synonymous GLI2 variants were identified in 24 patients. Twenty-three patients had CPHD and one had IGHD. Two patients had additional diabetes insipidus, indicating deficiencies of anterior and posterior pituitary lobes. The posterior pituitary lobe on MRI was ectopic in 16, not visible in 4, normally placed in 2 and imaging was not available in two patients, but there were no signs of holoprosencephaly. Sixteen GLI2 variants were considered deleterious in at least one of the prediction sites. Conclusions A relatively high frequency of non-synonymous GLI2 variants was identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with CPHD and an ectopic posterior pituitary lobe. In vitro functional assays may contribute to ascertain the deleterious consequences of these variants.
- Absence of GH-Releasing Hormone (GHRH) Mutations in Selected Patients with Isolated GH Deficiency(2011) FRANCA, Marcela M.; JORGE, Alexander A. L.; ALATZOGLOU, Kyriaki S.; CARVALHO, Luciani R. S.; MENDONCA, Berenice B.; AUDI, Laura; CARRASCOSA, Antonio; DATTANI, Mehul T.; ARNHOLD, Ivo J. P.Context: Although numerous reports of mutations in GH1 and GHRHR (GHRH receptor) causing isolated GH deficiency (IGHD) have been published, mutations in GHRH itself have not been hitherto reported but are obvious candidates for GH deficiency. Objective: The aim of this study was to identify mutations in GHRH in a large cohort of patients with IGHD. Patients and Methods: DNA was isolated from 151 patients diagnosed with IGHD at national and international centers. Seventy-two patients fulfilled all the following criteria: severe short stature (height SD score <= -2.5), low peakGHafter stimulation (peak <= 5 ng/ml), eutopic posterior pituitary lobe, and absence of mutations in GH1 and GHRHR and therefore were strong candidates for GHRH mutations. The coding sequence and splice sites of GHRH were amplified by PCR with intronic primers and sequenced. Results: In five of 151 patients (four of 42 from Brazil), the GHRH c. 223 C>T, p. L75F change was identified in heterozygosity. This variant has been previously reported as a polymorphism and is more frequent in African than European and Asian populations. Six allelic variants (five novel) that do not predict change of amino acids or splice sites were identified in five patients: c. 147 C>T, p.S49S, IVS1 -70 G>A, IVS1 -74 T>C, IVS3 -47 del1, and IVS3 +7 G>A/IVS3 + 41 G>A. No functional mutations were found in this cohort. Conclusions: GHRH mutations were not identified in a selected cohort of patients with IGHD, suggesting that, if they exist, they may be an extremely rare cause of IGHD. Other, as-yet-unidentified genetic factors may be implicated in the genetic etiology of IGHD in our cohort. (J Clin Endocrinol Metab 96: E1457-E1460, 2011)
conferenceObject Successful Pregnancies after Adequate Hormonal Replacement Prior to Ovarian Stimulation in Four Patients with Congenital Hypopituitarism(2014) CORREA, Fernanda de Azevedo; BIANCHI, Paulo H. M.; FRANCA, Marcela M.; OTTO, Aline P.; RODRIGUES, Rodrigo J. M.; EJZENBERG, Dani; SERAFINI, Paulo C.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; CARVALHO, Luciani R. S.- Growth hormone pharmacogenetics: the interactive effect of a microsatellite in the IGF1 promoter region with the GHR-exon 3 and-202 A/C IGFBP3 variants on treatment outcomes of children with severe GH deficiency(2012) COSTALONGA, E. F.; ANTONINI, S. R. R.; GUERRA-JUNIOR, G.; COLETTA, R. R. D.; FRANCA, M. M.; BRAZ, A. F.; MENDONCA, B. B.; ARNHOLD, I. J. P.; JORGE, A. A. L.Insulin-like growth factor type 1 (IGF1) is a mediator of growth hormone (GH) action, and therefore, IGF1 is a candidate gene for recombinant human GH (rhGH) pharmacogenetics. Lower serum IGF1 levels were found in adults homozygous for 19 cytosine-adenosine (CA) repeats in the IGF1 promoter. The aim of this study was to evaluate the influence of (CA)n IGF1 polymorphism, alone or in combination with GH receptor (GHR)-exon 3 and -202 A/C insulin-like growth factor binding protein-3 (IGFBP3) polymorphisms, on the growth response to rhGH therapy in GH-deficient (GHD) patients. Eighty-four severe GHD patients were genotyped for (CA) n IGF1, -202 A/C IGFBP3 and GHR-exon 3 polymorphisms. Multiple linear regressions were performed to estimate the effect of each genotype, after adjustment for other influential factors. We assessed the influence of genotypes on the first year growth velocity (1st y GV) (n = 84) and adult height standard deviation score (SDS) adjusted for target-height SDS (AH-TH SDS) after rhGH therapy (n = 37). Homozygosity for the IGF1 19CA repeat allele was negatively correlated with 1st y GV (P = 0.03) and AH-TH SDS (P = 0.002) in multiple linear regression analysis. In conjunction with clinical factors, IGF1 and IGFBP3 genotypes explain 29% of the 1st y GV variability, whereas IGF1 and GHR polymorphisms explain 59% of final height-target-height SDS variability. We conclude that homozygosity for IGF1 (CA) 19 allele is associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with severe GHD. Furthermore, this polymorphism exhibits a non-additive interaction with -202 A/C IGFBP3 genotype on the 1st y GV and with GHR-exon 3 genotype on adult height. The Pharmacogenomics Journal (2012) 12, 439-445; doi:10.1038/tpj.2011.13; published online 5 April 2011
bookPart Deficiências hipotálamo-hipofisárias múltiplas por mutações no gene GLI2(2012) FRANçA, Marcela M.; JORGE, Alexander Augusto de Lima; ARNHOLD, Ivo Jorge PradoconferenceObject A Novel OTX2 Mutation, p.H230L, Causes Hypopituitarism with Incomplete Penetrance: Exome Sequencing to Identify Modifier Genes(2014) FOYOUZI, Nastaran; CAMPER, Sally Ann; MOREIRA, Michele; FRANCA, Marcela M.; OTTO, Aline P.; CORREA, Fernanda de Azevedo; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; MA, Qianyi; LI, Jun Z.; FANG, Qing; CARVALHO, Luciani R. S.