Clinical, biochemical and molecular investigation of Thyrotoxic periodic paralysis

• Grant number: 11/20747-8
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2012
• End date: January 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Magnus Régios Dias da Silva
• Grantee: Magnus Régios Dias da Silva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Manoel de Arcisio Miranda Filho

Abstract

Thyrotoxic periodic paralysis (TPP) is a clinical condition characterized by reversible attacks of muscle weakness associated with thyrotoxicosis and hypokalemia. It is the most frequent cause of acute flaccid paralysis acquired in adults, albeit more prevalent among Asians and Latin American men. The pathophysiology of TPP is still unclear, but some evidences suggest that the TPP raises is a combination of three factors: environmental, genetic and thyrotoxicosis, the latter being essential to the crisis and that is independent of the etiology of hyperthyroidism. During the last ten years our group has been studied the etiology, epidemiology, clinical presentation and diagnosis, pathophysiology, treatment and, in particular, the molecular aspects that makes hyperthyroid patients susceptible to muscle paralysis. Today we have figured it out that TPP is the newest form of an endocrine channelopathy, and part of a large group of periodic paralyses. We believe that the TPP is a multigenic susceptibility neuromuscular disorder (genetic heterogeneity) in which only a subset of patients with mutation develop muscle weakness crisis. In the way of searching TPP susceptibility, our group went looking for mutations in several genes for ion channels and found a new gene that we named as KCNJ18 (Kir2.6 channel), one of the Kir paralogs. Four different mutations were identified (T354M, K366R, Q407X and R399X) and are present in 33% of patients. In this project we propose to study 11 other genes as new candidates among the 87 channels which were pulled out through their expression in skeletal muscle, response to hyperinsulinemia and also those presenting consensus elements (cis) responsive to thyroid hormone (Thyroid Responsive Elements - TRE) and/or androgen (Androgen Responsive Elements - ARE) in their regulatory region. We also aim at studying the potassium K-ATP channels in skeletal muscle, which in contrast to individuals susceptible to diabetes, its variants E23K in Kir6.1 (gene KCNJ11) and S1369A in SUR1 (gene ABCC8) predispose to type 2 diabetes, patients with TPP and, therefore, hyperinsulinemic, would inherit the A wild-type allele of the KCNJ11 gene and / or the S allele of the gene ABCC8. We will also investigate how the condition of hyperinsulinemia in patients with TPP could increase glucose uptake and therefore increase the sequestration of intracellular potassium into muscle, leading to hypokalaemia and paralysis. Indeed, we will also study if the Kir2.6, paralogs similar to Kir6.1 and Kir6.2, assembles with SUR subunit to form the muscle K-ATP in the condition of hyperthyroidism. We want to demonstrate in vitro that the Kir2.6 and SUR subunit of the K-ATP channel are greatly regulated by insulin /carbohydrate dynamics, together with testosterone and excess T3. We also intend to demonstrate study electrophysiologically whether the potassium channel mutants are able to trap potassium inside sarcolemma and then causing hypokalemia and flaccid paralysis. We also plan to explore feline genome (cat) as an animal genetic model due to its similarities to TPP in humans, through which we aim at cloning Kir2.6 ortholog channel and verifying the inheritance pattern in hyperthyroid cats with ventroflexion of neck and muscle paralysis. (AU)

Scientific publications

(15)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZAPATA, MARLYN; KUNII, ILDA S.; PANINKA, ROLF M.; SIMOES, DENISE M. N.; CASTILLO, VICTOR A.; RECHE, JR., ARCHIVALDO; MACIEL, RUI M. B.; DA SILVA, MAGNUS R. DIAS. Molecular cloning of ion channels in Felis catus that are related to periodic paralyses in man: a contribution to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis. BIOLOGY OPEN, v. 3, n. 9, p. 785-793, SEP 15 2014. (11/20747-8)

DOTTO, RENATA P.; GIUFFRIDA, FERNANDO M. A.; FRANCO, LUCIANA; MATHEZ, ANDREIA L. G.; WEINERT, LETICIA S.; SILVEIRO, SANDRA P.; SA, JOAO R.; REIS, ANDRE F.; DIAS-DA-SILVA, MAGNUS R.. Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations. Diabetes Research and Clinical Practice, v. 116, p. 100-104, JUN 2016. (15/05123-9, 11/20747-8)

CAMACHO, CLEBER P.; LINDSEY, SUSAN C.; MELO, MARIA CLARA C.; YANG, JI H.; GERMANO-NETO, FAUSTO; VALENTE, FLAVIA DE O. F.; LIMA, THIAGO R. N.; BISCOLLA, ROSA PAULA M.; VIEIRA, JOSE G. H.; CERUTTI, JANETE M.; et al. Measurement of Calcitonin and Calcitonin Gene-Related Peptide mRNA Refines the Management of Patients with Medullary Thyroid Cancer and May Replace Calcitonin-Stimulation Tests. THYROID, v. 23, n. 3, p. 308-316, MAR 2013. (11/20747-8, 06/60402-1, 09/11257-7)

SIVIERO-MIACHON, ADRIANA A.; KIZYS, MARINA M. L.; RIBEIRO, MANUELA M.; GARCIA, FABIOLA ESGRIGNOLI; SPINOLA-CASTRO, ANGELA M.; DIAS DA SILVA, MAGNUS R.. Cosegregation of a novel mutation in the sixth transmembrane segment of the luteinizing/choriogonadotropin hormone receptor with two Brazilian siblings with severe testotoxicosis. ENDOCRINE RESEARCH, v. 42, n. 2, p. 117-124, 2017. (06/60402-1, 11/20747-8, 14/15948-2, 12/01628-0)

KIZYS, MARINA M. L.; CARDOSO, MIRIAN G.; LINDSEY, SUSAN C.; HARADA, MICHELLE Y.; SOARES, FERNANDO A.; MELO, MARIA CLARA C.; MONTOYA, MARLYN Z.; KASAMATSU, TERESA S.; KUNII, ILDA S.; GIANNOCCO, GISELE; et al. Otimização da extração de ácidos nucleicos de material de punção aspirativa por agulha fina de tiroide obtido de lâminas coradas, tecidos fixados em formalina e emblocados em parafina e amostras de sangue estocadas por longo período. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 56, n. 9, p. 618-626, DEC 2012. (11/20747-8, 06/60402-1, 10/19834-0)

WEINERT, LETICIA S.; SILVEIRO, SANDRA P.; GIUFFRIDA, FERNANDO M. A.; CUNHA, VIVIAN T.; BULCAO, CAROLINE; CALLIARI, LUIS EDUARDO; DELLA MANNA, THAIS; KUNII, ILDA S.; DOTTO, RENATA P.; DIAS-DA-SILVA, MAGNUS R.; et al. Three unreported glucokinase (GCK) missense mutations detected in the screening of thirty-two Brazilian kindreds for GCK and HNF1A-MODY. Diabetes Research and Clinical Practice, v. 106, n. 2, p. E44-E48, NOV 2014. (11/20747-8)

ROLIM, ANA LUIZA R.; LINDSEY, SUSAN C.; KUNII, ILDA S.; CRISPIM, FELIPE; MOISES, REGINA CELIA M. S.; MACIEL, RUI M. B.; DIAS-DA-SILVA, MAGNUS R.. The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis. JOURNAL OF MOLECULAR ENDOCRINOLOGY, v. 53, n. 2, p. 295-301, OCT 2014. (06/60402-1, 11/20747-8)

PANINKA, ROLF M.; MAZZOTTI, DIEGO R.; KIZYS, MARINA M. L.; VIDI, ANGELA C.; RODRIGUES, HELIO; SILVA, SILAS P.; KUNII, ILDA S.; FURUZAWA, GILBERTO K.; ARCISIO-MIRANDA, MANOEL; DIAS-DA-SILVA, MAGNUS R.. Whole genome and exome sequencing realignment supports the assignment of KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic paralysis locus: functional characterization of two polymorphic Kir2.6 isoforms. Molecular Genetics and Genomics, v. 291, n. 4, p. 1535-1544, AUG 2016. (11/20747-8, 10/52077-9)

PANINKA, ROLF MATIAS; CARLOS-LIMA, ESTEVAO; LINDSEY, SUSAN C.; KUNII, ILDA S.; DIAS-DA-SILVA, MAGNUS R.; ARCISIO-MIRANDA, MANOEL. DOWN-REGULATION OF Kir2.6 CHANNEL BY C-TERMINI MUTATION D252N AND ITS ASSOCIATION WITH THE SUSCEPTIBILITY TO THYROTOXIC PERIODIC PARALYSIS. Neuroscience, v. 346, p. 197-202, MAR 27 2017. (11/20747-8, 10/52077-9)

KIZYS, MARINA M. L.; NESI-FRANCA, SUZANA; CARDOSO, MIRIAN G.; HARADA, MICHELLE Y.; MELO, MARIA CLARA C.; CHIAMOLERA, MARIA IZABEL; DIAS-DA-SILVA, MAGNUS R.; MACIEL, RUI M. B.. The absence of mutations in homeobox candidate genes HOXA3, HOXB3, HOXD3 and PITX2 in familial and sporadic thyroid hemiagenesis. JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, v. 27, n. 3-4, p. 317-322, MAR 2014. (12/00079-3, 11/20747-8, 12/02465-8, 12/01628-0)

NASCIMENTO, FABRICIO P.; CARDOSO, MIRIAN G.; LINDSEY, SUSAN C.; KUNII, ILDA S.; VALENTE, FLAVIA O. F.; KIZYS, MARINA M. L.; DELCELO, ROSANA; CAMACHO, CLEBER P.; MACIEL, RUI M. B.; DIAS-DA-SILVA, MAGNUS R.. Analysis of somatic mutations in BRAF, CDKN2A/p16 and PI3KCA in patients with medullary thyroid carcinoma. MOLECULAR MEDICINE REPORTS, v. 13, n. 2, p. 1653-1660, FEB 2016. (11/20747-8, 12/02465-8, 12/11036-3, 12/00079-3, 12/01628-0)

DOS SANTOS, LIVIA MARCELA; GUERRA, RICARDO AYELLO; LAZARETTI-CASTRO, MARISE; VIEIRA, JOSE GILBERTO H.; PORTES, EVANDRO DE SOUZA; DIAS-DA-SILVA, MAGNUS R.. An approach to the diagnosis and management of a case presenting with recurrent hypomagnesemia secondary to the chronic use of a proton pump inhibitor. MAGNESIUM RESEARCH, v. 28, n. 4, p. 136-145, DEC 2015. (11/20747-8)

CARVALHEIRA, GIANNA; MALINVERNI, ANDREA M.; MOYSES-OLIVEIRA, MARIANA; UETA, RENATA; CARDILI, LEONARDO; MONTEAGUDO, PATRICIA; MATHEZ, ANDREIA L. G.; VERRESCHI, IEDA T.; MALUF, MIGUEL A.; SHIDA, MARCIA E. F.; et al. The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene. JOURNAL OF THE ENDOCRINE SOCIETY, v. 3, n. 11, p. 2107-2113, NOV 2019. (14/11572-8, 11/20747-8, 12/00079-3, 14/06570-6)

VARGAS, MICHELLE CERUTTI C.; MOURA, FELIPE SCIPIAO; ELIAS, CECILIA P.; CARVALHO, SARA R.; RASSI, NELSON; KUNII, ILDA S.; DIAS-DA-SILVA, MAGNUS R.; COSTA-BARBOSA, FLAVIA AMANDA. Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutation. BMC Endocrine Disorders, v. 20, n. 1, FEB 6 2020. (11/20747-8, 14/06570-6)

MELO, MARIA CLARA C.; DE SOUZA, JANAINA S.; KIZYS, MARINA M. L.; VIDI, ANGELA C.; DORTA, HARON S.; KUNII, ILDA S.; GIANNOCCO, GISELE; CARVALHEIRA, GIANNA; DIAS-DA-SILVA, MAGNUS R.. Novel lincRNA Susceptibility Gene and Its Role in Etiopathogenesis of Thyrotoxic Periodic Paralysis. JOURNAL OF THE ENDOCRINE SOCIETY, v. 1, n. 7, p. 809-815, JUL 1 2017. (11/20747-8, 12/01628-0)