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1.
Genes (Basel) ; 10(11)2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703244

RESUMO

Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3-9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.

3.
Endocr Connect ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557724

RESUMO

Primary hyperparathyroidism is the most frequent manifestation of Multiple Endocrine Neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long-term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). 89 patients (49 men and 40 women, 34.2 + 13 years old) were included. 64 out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs. 7/12, p<0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypoparathyroidism and patients with different mutated exons, but a second surgery was more frequent after a less than subtotal parathyroidectomy.

5.
Head Neck ; 41(1): 79-91, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30549360

RESUMO

BACKGROUND: Succinate dehydrogenase subunit B (SDHB) immunohistochemistry was considered a valuable tool to identify patients with inherited paraganglioma/pheochromocytoma (PGL/PCC). However, previous studies jointly analyzed 2 related but clinically distinct entities, parasympathetic head and neck paragangliomas (HNPGLs) and sympathetic PCCs/PGLs. Additionally, a role for hypoxia inducible factor-1α (HIF-1α) as a biomarker for succinate dehydrogenase (SDHx)-mutated tumors has not been studied. Here, we evaluated the utility of SDHB/HIF-1α proteins in HNPGLs and PCCs/PGLs as clinically useful biomarkers. METHODS: The SDHB/succinate dehydrogenase subunit A (SDHA)/HIF-1α immunohistochemistry analysis was performed in 158 genetically defined patients. RESULTS: Similarly to PCCs/PGLs, SDHB immune-negativity correlated with SDHx-mutations in HNPGLs (P < .0001). The HIF-1α stabilization was associated with SDHx-mutations in HNPGLs (P = .020), not in PCCs/PGLs (P = .319). However, 25% of SDHx-HNPGLs lacked HIF-1α positive cells. CONCLUSION: As in PCCs/PGLs, SDHB immunohistochemistry in HNPGLs is a valuable method for identification of candidates for SDHx-genetic testing. On the contrary, although SDHx mutations may favor HIF-1α stabilization in HNPGLs, this is not a clinically useful biomarker.

6.
Biochim Biophys Acta Mol Basis Dis ; 1864(7): 2385-2394, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29704611

RESUMO

Glucokinase (GCK) plays a key role in glucose homeostasis. Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Besides its particular kinetic characteristics, glucokinase is regulated by subcellular compartmentation in hepatocytes. Glucokinase regulatory protein (GKRP) binds to GCK, leading to enzyme inhibition and import into the nucleus at fasting. When glucose concentration increases, GCK-GKRP dissociates and GCK is exported to the cytosol due to a nuclear export signal (NES). With the aim to characterize the GCK-NES, we have functionally analysed nine MODY2 mutations located within the NES sequence. Recombinant GCK mutants showed reduced catalytic activity and, in most cases, protein instability. Most of the mutants interact normally with GKRP, although mutations L306R and L309P impair GCK nuclear import in cotransfected cells. We demonstrated that GCK-NES function depends on exportin 1. We further showed that none of the mutations fully inactivate the NES, with the exception of mutation L304P, which likely destabilizes its α-helicoidal structure. Finally, we found that residue Glu300 negatively modulates the NES activity, whereas other residues have the opposite effect, thus suggesting that some of the NES spacer residues contribute to the low affinity of the NES for exportin 1, which is required for its proper functioning. In conclusion, our results have provided functional and structural insights regarding the GCK-NES and contributed to a better knowledge of the molecular mechanisms involved in the nucleo-cytoplasmic shuttling of glucokinase. Impairment of this regulatory mechanism by some MODY2 mutations might contribute to the hyperglycaemia in the patients.


Assuntos
Núcleo Celular/enzimologia , Citoplasma/enzimologia , Diabetes Mellitus Tipo 2 , Glucoquinase , Hepatócitos/enzimologia , Mutação de Sentido Incorreto , Sinais de Exportação Nuclear/genética , Adulto , Substituição de Aminoácidos , Núcleo Celular/patologia , Citoplasma/patologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Feminino , Glucoquinase/genética , Glucoquinase/metabolismo , Células HEK293 , Humanos , Carioferinas/genética , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
9.
JIMD Rep ; 20: 21-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25665835

RESUMO

BACKGROUND: Hypoglycaemic drugs that close the KATP channel have been tested in patients with permanent neonatal diabetes due to glucokinase mutations (PNDM-GCK). From the results obtained, it has been suggested that this treatment may be beneficial in patients carrying GCK mutations with mild kinetic defects. The aim of this study was to evaluate the kinetic analysis of glucokinase activity as a predictive factor for response to sulphonylureas in PNDM-GCK. METHODS: The clinical characteristics of two siblings with PNDM born to non-consanguineous parents are described. Mutation analysis of KCNJ11, INS and GCK genes was done by sequencing. A comprehensive functional characterisation of GCK mutation was undertaken. Glibenclamide treatment was assayed for 16 weeks in one child. Response to treatment was evaluated by means of fasting glycaemia, C-peptide and HbA1c levels. RESULTS: Compound heterozygous GCK mutations (p.Ile19Asn and p.Ser441Trp) were identified. Functional analysis of GCK(p.Ile19Asn) indicated that this mutant retained more than 70% of wild-type catalytic activity in vitro, with a slight increase of thermolability. This mutation did not impair the interaction with the glucokinase regulatory protein, and the enzymatic activity of the GCK(p.Ile19Asn) mutant is restored to wild-type levels in the presence of GCK allosteric activator LY2121260. However, glibenclamide treatment of the patient on a reduced dose of insulin did not reduce HbA1c levels, and C-peptide increased only very slightly. CONCLUSION: Hypoglycaemic drugs acting on the KATP channel might not be useful in the treatment of PNDM-GCK, even in patients carrying GCK mutations with mild kinetic defects.

11.
Hormones (Athens) ; 13(1): 74-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24722129

RESUMO

OBJECTIVE: The aim of the study was to describe the clinical, biochemical, and genetic features of a sample of Mediterranean patients with RTH (resistance to thyroid hormone) due to mutations in TRß (thyroid hormone receptor beta) referred to our institution during the last 15 years. DESIGN: 166 blood samples were received for RTH genetic testing between January 1997 and December 2011. Genetic testing was performed by PCR amplification followed by sequencing of exons 7, 8, 9, and 10. Clinical and biochemical features were obtained from available information sent by referring hospitals. RESULTS: Mutations were identified in 50 patients (29 probands and 21 relatives). 64% were women, and mean ± stdev age at diagnosis among probands was 33.2 ± 20.5 years. The following clinical features were recorded: goiter in 50%, hyperkinetic behavior in 32%, and tachycardia in 29%. Up to 19% of the probands had undergone some type of thyroidal ablative therapy before diagnosis. As for biochemical features, mean ± stdev TSH was 10.2 ± 21.4 mUI/L, and mean ± stdev fT4 was 35.5 ± 10.8 pmol/L. We found four new mutations: p.Phe451Leu, p.Pro452Arg, p.Glu457Gly, and p.Phe459Leu. CONCLUSIONS: The clinical and biochemical characteristics of our samples of Mediterranean populations with RTH were similar to those described in the published literature. Interestingly, in our populations we have identified four novel mutations in the TRß gene.


Assuntos
Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Bócio/genética , Grécia , Humanos , Hipercinese/genética , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Espanha , Taquicardia/genética , Adulto Jovem
12.
Nefrología (Madr.) ; 34(2): 212-215, mar.-abr. 2014. tab
Artigo em Espanhol | IBECS | ID: ibc-124778

RESUMO

Antecedentes: Pocos trabajos han estudiado la asociación entre el genotipo de la haptoglobina (Hp) y el riesgo de nefropatía diabética (ND) en pacientes con diabetes tipo 1 (DM1), con resultados contradictorios hasta ahora.Objetivos: Estudiar si el genotipo 2-2 de Hp se asocia a un incremento del riesgo de ND en población española con DM1. Métodos: Se diseñó un estudio de casos y controles. CASOS: pacientes con DM1 y enfermedad renal crónica estadio 5 de la NKF-KDOQI, en espera de trasplante reno-pancreático o que han sido trasplantados (reno-pancreático o renal aislado). CONTROLES: pacientes con DM1, apareados por sexo y tiempo de evolución de la diabetes, con función renal y excreción urinaria de albúmina normales. El genotipo de Hp se realizó mediante reacción en cadena de la polimerasa y electroforesis. Resultados: Incluimos 57 casos y 57 controles, sin diferencias estadísticamente significativas en el sexo (70 % frente a 61 % varones, p = 1,0) o duración de la diabetes (23,0 ± 6,7 frente a 20,8 ± 9,3 años; p = 0,1), aunque la edad de inicio de la diabetes fue menor en los casos (14,1 ± 6,8 frente a 17,7 ± 10,1 años, p = 0,03). La frecuencia de genotipos 1-1, 1-2 y 2-2 fue de 19,3 %, 42,1 % y 38,6 % en los casos y de 17,5 %, 49,1 % y 33,4 % en los controles, respectivamente, sin diferencias significativas (p = 0,8). El análisis de regresión logística condicional no mostró asociación entre el genotipo 2-2 de Hp y el desarrollo de ND (OR 1,14, IC 0,52-2,52). Conclusiones: En nuestra muestra de población española con DM1, no se ha hallado asociación entre el genotipo de Hp y el riesgo de ND (AU)


Background: Few reports have studied the possible association between the haptoglobin (Hp) genotype and the risk of diabetic nephropathy (DN) in type 1 diabetes (T1D), with conflicting results to date. Aims: To study whether the 2-2 Hp genotype is associated with an increased risk of overt DN in a Spanish population with T1D. Methods: We performed a case-control study in a Spanish population. CASES: T1D patients with end-stage renal disease (stage 5 of NKF-KDOQI), awaiting reno-pancreatic transplantation or having already been transplanted (reno-pancreatic or renal alone). CONTROLS: T1D patients, matched for sex and time of diabetes evolution, with preserved renal function and normal urinary albumin excretion. Hp genotyping was done using polymerase chain reaction and electrophoresis. Results: We included 57 cases and 57 controls in the study. There were no statistically significant differences in gender (70% vs. 61% males, p=1.0) or the duration of diabetes (23.0±6.7 vs. 20.8±9.3 years; p=0.1), although the age of onset of diabetes was lower in the cases (14.1±6.8 vs. 17.7±10.1 years, p=0.03). The frequency of genotypes 1-1, 1-2 and 2-2 was 19.3%, 42.1% and 38.6% in cases and 17.5%, 49.1% and 33.4% in controls, respectively, with no statistically significant differences between groups (p=0.8). Conditional logistic regression analysis showed no significant association between genotype 2-2 of Hp and the development of DN (OR 1.14, CI 0.52-2.52). Conclusions: In our sample of a Spanish population with T1D, no association was found between the Hp genotype and risk of overt DN (AU)


Assuntos
Humanos , Haptoglobinas/análise , Nefropatias Diabéticas/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Falência Renal Crônica/epidemiologia , Técnicas de Genotipagem , Marcadores Genéticos
13.
Nefrologia ; 34(2): 212-5, 2014.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-24658196

RESUMO

BACKGROUND: Few reports have studied the possible association between the haptoglobin (Hp) genotype and the risk of diabetic nephropathy (DN) in type 1 diabetes (T1D), with conflicting results to date. AIMS: To study whether the 2-2 Hp genotype is associated with an increased risk of overt DN in a Spanish population with T1D. METHODS: We performed a case-control study in a Spanish population. CASES: T1D patients with end-stage renal disease (stage 5 of NKF-KDOQI), awaiting reno-pancreatic transplantation or having already been transplanted (reno-pancreatic or renal alone). CONTROLS: T1D patients, matched for sex and time of diabetes evolution, with preserved renal function and normal urinary albumin excretion. Hp genotyping was done using polymerase chain reaction and electrophoresis. RESULTS: We included 57 cases and 57 controls in the study. There were no statistically significant differences in gender (70% vs. 61% males, p=1.0) or the duration of diabetes (23.0 ± 6.7 vs. 20.8 ± 9.3 years; p=0.1), although the age of onset of diabetes was lower in the cases (14.1 ± 6.8 vs. 17.7 ± 10.1 years, p=0.03). The frequency of genotypes 1-1, 1-2 and 2-2 was 19.3%, 42.1% and 38.6% in cases and 17.5%, 49.1% and 33.4% in controls, respectively, with no statistically significant differences between groups (p=0.8). Conditional logistic regression analysis showed no significant association between genotype 2-2 of Hp and the development of DN (OR 1.14, CI 0.52-2.52). CONCLUSIONS: In our sample of a Spanish population with T1D, no association was found between the Hp genotype and risk of overt DN.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/genética , Haptoglobinas/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Risco , Espanha
14.
Hormones (Athens) ; 12(3): 466-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24121389

RESUMO

Always granting that de novo mutations are possible, family history and biological characteristics are nonetheless crucial for the diagnosis of monogenic diabetes. We report here the case of two patients with monogenic diabetes in which the initial family history misled the diagnostic work-up and did not support the diagnosis. Family history details changed substantially after the molecular diagnosis was established.


Assuntos
Diabetes Mellitus/diagnóstico , Erros de Diagnóstico , Família , Adulto , Peso ao Nascer , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Feminino , Deleção de Genes , Glucoquinase/genética , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Recém-Nascido , Masculino
15.
Arch Esp Urol ; 66(5): 409-15, 2013 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-23793758

RESUMO

Molecular biology has been one of the scientific disciplines in which there has been more advances in the last years. The first impulse in the study of genetic alterations came from the discovery of DNA structure, followed by elucidation of the genetic code, the discovery of restriction enzymes and subsequently the invention of PCR, not forgetting the exponential development of computer science. All of them have allowed us to know much more about our genome and its regulation than we could imagine. The impulse in proteomics has been especially in tune up of soft methods of ionization coupled with mass spectrometry. Nevertheless, this seems to be only the beginning since today there are continuous methodological advances that will increase more, without doubt, the knowledge and applications in this discipline.


Assuntos
Oncologia/métodos , Biologia Molecular/métodos , Urologia/métodos , Animais , Pesquisa Biomédica , DNA/genética , DNA de Neoplasias/genética , Humanos , Proteínas de Neoplasias/genética , RNA/genética , RNA Neoplásico/genética
16.
Arch. esp. urol. (Ed. impr.) ; 66(5): 409-415, jun. 2013.
Artigo em Espanhol | IBECS | ID: ibc-113254

RESUMO

La Biología Molecular ha sido una de las disciplinas científicas en las que se ha avanzado más en los últimos años. El primer impulso en el estudio de alteraciones genéticas, provino del descubrimiento de la estructura del DNA, seguido de la dilucidación del código genético, del descubrimiento de los enzimas de restricción y luego, de la invención de la PCR, sin olvidar por supuesto del exponencial desarrollo de la informática. Todo ello nos ha permitido conocer mucho más acerca de nuestro genoma y su regulación de lo que podíamos imaginar. El impulso en proteómica ha sido sobretodo la puesta a punto de métodos suaves de ionización acoplados a la espectrometría de masas. Sin embargo esto parece ser solo el comienzo ya que hoy en día continúan habiendo avances metodológicos que sin duda aumentarán aun más los conocimientos y las aplicaciones en esta disciplina (AU)


Molecular biology has been one of the scientific disciplines in which there has been more advances in the last years. The first impulse in the study of genetic alterations came from the discovery of DNA structure, followed by elucidation of the genetic code, the discovery of restriction enzymes and subsequently the invention of PCR, not forgetting the exponential development of computer science. All of them have allowed us to know much more about our genome and its regulation than we could imagine. The impulse in proteomics has been especially in tune up of soft methods of ionization coupled with mass spectrometry. Nevertheless, this seems to be only the beginning since today there are continuous methodological advances that will increase more, without doubt, the knowledge and applications in this discipline (AU)


Assuntos
Humanos , Biologia Molecular/métodos , Neoplasias Urológicas/genética , Biomarcadores Tumorais/análise , Proteômica/métodos , Genômica/métodos , Espectrometria de Massas/métodos , Detecção Precoce de Câncer/métodos
18.
Artigo em Inglês | MEDLINE | ID: mdl-24683474

RESUMO

BACKGROUND: Thyroid hormone resistance (RTH) is a rare cause of thyroid dysfunction. High TSH levels, as described in RTH syndrome, are known to be associated with an increased risk of developing thyroid nodules with subsequent growth and malignancy. PATIENT FINDINGS: In 2006, a 29-year-old Caucasian man presented with a palpable mass in the neck. Increased free thyroxine and triiodothyronine levels were found in the context of unsuppressed TSH levels, despite no signs or symptoms of hyperthyroidism. Ultrasonography revealed a multinodular and enlarged goitre, and fine-needle aspiration cytology revealed suspicious features of malignancy. After excluding pituitary tumour and levothyroxine (l-T4) treatment, the patient was diagnosed with generalized RTH. Screening for all the known mutations in thyroid hormone receptor-ß (TR ß (THRB)) was negative. Thyroidectomy disclosed five Hürthle adenomas and three hyperplasic nodules. Euthyroidism was achieved after surgery with 6.1 µg/kg per day of l-T4. CONCLUSION: RTH may be a risk factor that predisposes to the development of multiple Hürthle cell adenomas. To our knowledge, this is the first case of multiple Hürthle cell adenomas in a patient with RTH. LEARNING POINTS: High TSH levels, as described in RTH syndrome, are known to be associated with an increased risk of developing thyroid nodules, with subsequent growth and malignancy.The exact role of TR ß mutants in thyroid carcinogenesis is still undefined.We report the first case of multiple Hürthle cell adenomas associated with RTH.

19.
Eur J Endocrinol ; 168(1): 9-13, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23038625

RESUMO

OBJECTIVE: Most cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment. DESIGN AND METHODS: Fifty patients with acromegaly (22 males/28 females, age 51±18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification. RESULTS: SEQUENCE CHANGES OF POTENTIAL DIFFERENT SIGNIFICANCE THAT COULD BE CONSIDERED AS MUTATIONS OR VARIATIONS OF UNKNOWN SIGNIFICANCE (VUS) OF THE AIP GENE WERE FOUND IN FOUR PATIENTS (8%). IN TWO CASES, TWO DIFFERENT MUTATIONS PREVIOUSLY DESCRIBED WERE FOUND: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment. CONCLUSIONS: AIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues.


Assuntos
Acromegalia/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Adenoma/genética , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos , Feminino , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico
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