MARIANA FERREIRA DE ASSIS FUNARI
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject NOVEL LZTR1 GENE VARIANTS ASSOCIATED TO NOONAN SYNDROME AND GROWTH HORMONE DEFICIENCY(2017) NAKAGUMA, Marilena; JORGE, Alexander A. L.; MARIANA, Funari F. A.; ANTONIO, Lerario M.; FERNANDA, Correa A.; LUCIANI, Carvalho R. S.; BERENICE, Mendonca B.; ARNHOLD, Ivo J.- A novel homozygous 1-bp deletion in the NOBOX gene in two Brazilian sisters with primary ovarian failure(2017) FRANCA, Monica M.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; NISHI, Mirian Y.; PITA, Carmem C.; FONTENELE, Eveline G. P.; MENDONCA, Berenice B.Purpose Primary ovarian failure (POF) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women leading to infertility under the age of 40 years. POF is a heterogeneous disease with different causes, and several genes have been associated with the POF phenotype. Thus, Whole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by POF. Methods All exons of both sisters were massively sequenced by WES, and the segregation was confirmed by Sanger sequencing. Results The novel homozygous c.1489delT variant in the NOBOX gene was identified in the two sisters with POF. Their parents were heterozygous carriers of this variant and, therefore, consistent with an autosomal recessive mode of inheritance. The c.1489delT NOBOX variant has not been previously reported in any public available databases (1000Genomes, 6500ESP/EVS, ExAC, and gnomAD). Furthermore, this variant was neither present in 387 Brazilian exomes control individuals nor in 200 fertile Brazilian women screened by Sanger sequencing. Conclusion We report the first familial case of a novel homozygous NOBOX variant with an autosomal recessive mode of inheritance, thus allowing for a genetic diagnosis of primary ovarian failure.
- Evaluation of bone mineral density and microarchitectural parameters by DXA and HR-pQCT in 37 children and adults with X-linked hypophosphatemic rickets(2017) COLARES NETO, G. P.; PEREIRA, R. M. R.; ALVARENGA, J. C.; TAKAYAMA, L.; FUNARI, M. F. A.; MARTIN, R. M.In X-linked hypophosphatemic (XLH) rickets, dual-energy X-ray absorptiometry (DXA) measurements must be analyzed with caution. High-resolution peripheral quantitative computed tomography (HR-pQCT) analysis suggested that XLH primarily affects the cancellous compartment, with the tibia more affected than the radius. Effective treatment of XLH appears to positively affect bone mineralization, mainly in the bone cortex. The purpose of this study is to evaluate bone mineral density (BMD) and microarchitecture in 37 patients (13 children and 24 adults) with XLH confirmed by PHEX mutations from a tertiary center compared to healthy controls. Areal BMD (aBMD) was evaluated by DXA, whereas volumetric BMD (vBMD) and microarchitectural parameters were analyzed by HR-pQCT. Adult XLH patients had higher lumbar aBMD (p < 0.01) than the controls. At the radius, the vBMD was similar between XLH patients and controls. At the tibia, XLH patients had lower total vBMD (p = 0.04), likely resulting from decreased trabecular vBMD (p < 0.01), and this difference was observed in the children and adult groups. Analysis based on metabolic status showed that the adult XLH patients with non-compensated disease had lower cortical vBMD at the tibia than the compensated XLH patients (p = 0.03). The microarchitectural differences at the radius and tibia included lower trabecular number (p < 0.01), greater trabecular separation (p < 0.01), and higher trabecular network inhomogeneity (p < 0.01) in XLH patients compared to their controls. At the radius, adults exhibited greater trabecular deficits than were seen in children. In XLH patients, DXA measurements must be analyzed with caution due to the interference of anatomic and anthropometric factors. HR-pQCT analysis suggested that XLH primarily affects the cancellous compartment, with the tibia more affected than the radius. Effective treatment of XLH appears to positively affect bone mineralization, mainly in the bone cortex.
conferenceObject GROWTH HORMONE (GH) THERAPY IMPROVES ADULT HEIGHT IN CHILDREN WITH NOONAN SYNDROME AND IDENTIFIED MUTATIONS IN PTPN11 GENE(2017) NORONHA, Renata M.; HOMMA, Thais K.; SOUZA, Thaiana T.; FUNARI, Mariana; PEREIRA, Alexandre C.; BERTOLA, Debora; JORGE, Alexander; MALAQUIAS, Alexsandra C.conferenceObject GENOMIC APPROACHES TO INVESTIGATE CHILDREN BORN SMALL FOR GESTATIONAL AGE (SGA) WITHOUT CATCH UP-GROWTH(2017) HOMMA, Thais K.; FREIRE, Bruna; FUNARI, Mariana; MALAQUIAS, Alexsandra; RONJO, Rachel; VASQUES, Gabriela; CANTON, Ana; KIM, Chong; BERTOLA, Debora; JORGE, Alexander- Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2(2017) VASQUES, Gabriela A.; HISADO-OLIVA, Alfonso; FUNARI, Mariana F. A.; LERARIO, Antonio M.; QUEDAS, Elisangela P. S.; SOLBERG, Paulo; HEATH, Karen E.; JORGE, Alexander A. L.Background: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. Case presentation: The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8. Results: We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p. Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. Conclusions: This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.
- A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family(2017) FRANCA, Monica M.; LERARIO, Antonio M.; FUNARI, Mariana F. A.; NISHI, Mirian Y.; NARCIZO, Amanda M.; MELLO, Maricilda P. de; GUERRA-JUNIOR, Gil; MACIEL-GUERRA, Andrea T.; MENDONCA, Berenice B.Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46, XX girl and a 46, XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c. 1298C> A; p. Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/ EVS) and Brazilian exome controls.Moreover, it is highly conserved and predicted as deleteriousin all prediction sites analyzed. In conclusion, the novel homozygousFSHR variant observed in 2 siblings with HH canexpand the spectrum of FSHR mutations in humans. (C) 2017 S. Karger AG, Basel
- Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect(2017) SCALCO, Renata C.; GONCALVES, Fernanda T.; SANTOS, Hadassa C.; CARDENA, Mari M. S. G.; TONELLI, Carlos A.; FUNARI, Mariana F. A.; ARACAVA, Rosana M.; PEREIRA, Alexandre C.; FRIDMAN, Cintia; JORGE, Alexander A. L.Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping forSTAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.
- Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations(2017) GKOUROGIANNI, Alexandra; ANDREW, Melissa; TYZINSKI, Leah; CROCKER, Melissa; DOUGLAS, Jessica; DUNBAR, Nancy; FAIRCHILD, Jan; FUNARI, Mariana F. A.; HEATH, Karen E.; JORGE, Alexander A. L.; KURTZMAN, Tracey; LAFRANCHI, Stephen; LALANI, Seema; LEBL, Jan; LIN, Yuezhen; LOS, Evan; NEWBERN, Dorothee; NOWAK, Catherine; OLSON, Micah; POPOVIC, Jadranka; PRUHOVA, Stepanka; ELBLOVA, Lenka; QUINTOS, Jose Bernardo; SEGERLUND, Emma; SENTCHORDI, Lucia; SHINAWI, Marwan; STATTIN, Eva-Lena; SWARTZ, Jonathan; ANGEL, Ariadna Gonzalez del; CUELLAR, Sinhue Diaz; HOSONO, Hidekazu; SANCHEZ-LARA, Pedro A.; HWA, Vivian; BARON, Jeffrey; NILSSON, Ola; DAUBER, AndrewContext: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, + 1.3 years; range, + 0.0 to + 3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.