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Pesquisa : D12.776.543.990.150.500.750 [Categoria DeCS]
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[PMID]:28176280
[Au] Autor:Szalat A; Shpitzen S; Tsur A; Zalmon Koren I; Shilo S; Tripto-Shkolnik L; Durst R; Leitersdorf E; Meiner V
[Ad] Endereço:Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. auryans@hadassah.org.il.
[Ti] Título:Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia.
[So] Source:Endocrine;55(3):741-747, 2017 Mar.
[Is] ISSN:1559-0100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Patients with familial hyperparathyroidism and low urinary calcium excretion may have familial hypocalciuric hypercalcemia (FHH) with mutations in one of three genes: the calcium-sensing receptor (CaSR) defining FHH-type 1, the adaptor-related protein complex 2 (AP2S1) related to FHH-type 3 or the G-protein subunit alpha11 (GNA11) associated with FHH-type 2. We aimed to evaluate the presence of mutations in these genes and to identify phenotypic specificities and differences in these patients. SUBJECTS AND METHODS: Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of CaSR was done. In negative cases, we further performed sequencing of AP2S1 and GNA11. RESULTS: A total of 10 index cases were recruited. CaSR sequencing yielded three missense heterozygous mutations (30%): c.554G > A (p.I32V) previously characterized by our team, c.1394 G > A (p.R465Q) and a novel expected disease-causing mutation c.2479 A > C (p.S827R). We identified 2 additional patients (20%) carrying the deleterious recurrent mutation c.44G > T (p.R15L) in the AP2S1 gene. No GNA11 mutation was found. Clinically, patients with AP2S1 mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1. CONCLUSION: CaSR and AP2S1 sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases. GNA11 mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 rather than CaSR mutation and may guide the first step in the genetic evaluation.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Hipercalcemia/congênito
Mutação
Receptores de Detecção de Cálcio/genética
[Mh] Termos MeSH secundário: Adulto
Pré-Escolar
Feminino
Seres Humanos
Hipercalcemia/diagnóstico
Hipercalcemia/genética
Recém-Nascido
Masculino
Análise de Sequência com Séries de Oligonucleotídeos
Linhagem
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (CASR protein, human); 0 (GNA11 protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Receptors, Calcium-Sensing)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1007/s12020-017-1241-5


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[PMID]:27913609
[Au] Autor:Hovden S; Rejnmark L; Ladefoged SA; Nissen PH
[Ad] Endereço:Departments of Clinical Biochemistry.
[Ti] Título:AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia.
[So] Source:Eur J Endocrinol;176(2):177-185, 2017 Feb.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Familial hypocalciuric hypercalcemia (FHH) type 1 is caused by mutations in the gene encoding the calcium-sensing receptor (CASR). Recently, mutations affecting codon 15 in the gene AP2S1 have been shown to cause FHH type 3 in up to 26% of CASR-negative FHH patients. Similarly, mutations in the gene GNA11 have been shown to cause FHH type 2. We hypothesized that mutations in AP2S1 and GNA11 are causative in Danish patients with suspected FHH and that these mutations are not found in patients with primary hyperparathyroidism (PHPT), which is the main differential diagnostic disorder. DESIGN: Cross-sectional study. METHODS: We identified patients with unexplained hyperparathyroid hypercalcemia and a control group of verified PHPT patients through review of 421 patients tested for CASR mutations in the period 2006-2014. DNA sequencing of all amino acid coding exons including intron-exon boundaries in AP2S1 and GNA11 was performed. RESULTS: In 33 CASR-negative patients with suspected FHH, we found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype-phenotype correlations. We did not identify any pathogenic mutations in GNA11. No pathogenic mutations were found in the PHPT control group. CONCLUSIONS: We suggest that the best diagnostic approach to hyperparathyroid hypercalcemic patients suspected to have FHH is to screen the CASR and AP2S1 codon 15 for mutations. If the results are negative and there is still suspicion of an inherited condition (i.e. family history), then GNA11 should be examined.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Hipercalcemia/congênito
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Cálcio/metabolismo
Estudos Transversais
Seres Humanos
Hipercalcemia/genética
Meia-Idade
Mutação
Hormônio Paratireóideo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (GNA11 protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Parathyroid Hormone); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161204
[St] Status:MEDLINE


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[PMID]:27079945
[Au] Autor:Li X; Niu Y; Cheng M; Chi X; Liu X; Yang W
[Ad] Endereço:MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100176, China.
[Ti] Título:AP1S3 is required for hepatitis C virus infection by stabilizing E2 protein.
[So] Source:Antiviral Res;131:26-34, 2016 Jul.
[Is] ISSN:1872-9096
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Hepatitis C virus (HCV) infects 130 million people worldwide and is a leading cause of liver cirrhosis, end-stage liver disease and hepatocellular carcinoma. The interactions between viral elements and host factors play critical role on HCV invade, replication and release. Here, we identified adaptor protein complex 1 sigma 3 subunit (AP1S3) as a dependency factor for the efficient HCV infection in hepatoma cells. AP1S3 silencing in cultivated Huh7.5.1 cells significantly reduced the production of HCV progeny particles. Immunoprecipitation analysis revealed that AP1S3 interacted with the HCV E2 protein. With this interaction, AP1S3 could protect HCV E2 from ubiquitin-mediated proteasomal degradation. Using in vivo ubiquitylation assay, we identified that E6-Associated Protein (E6AP) was associated with HCV E2. In addition, treatment with synthetic peptide that contains the AP1S3-recognized motif inhibited HCV infection in Huh7.5.1 cells. Our data reveal AP1 as a novel host network that is required by viruses during infection and provides a potential target for developing broad-spectrum anti-virus strategies.
[Mh] Termos MeSH primário: Subunidades sigma do Complexo de Proteínas Adaptadoras/metabolismo
Hepacivirus/fisiologia
Interações Hospedeiro-Patógeno
Proteínas do Envelope Viral/metabolismo
[Mh] Termos MeSH secundário: Subunidades sigma do Complexo de Proteínas Adaptadoras/deficiência
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Carcinoma Hepatocelular/virologia
Linhagem Celular Tumoral
Inativação Gênica
Hepacivirus/efeitos dos fármacos
Seres Humanos
Imunoprecipitação
Neoplasias Hepáticas/virologia
Peptídeos/síntese química
Peptídeos/farmacologia
Complexo de Endopeptidases do Proteassoma/metabolismo
RNA Viral
Ubiquitina/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Montagem de Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP1S2 protein, human); 0 (Adaptor Protein Complex sigma Subunits); 0 (Peptides); 0 (RNA, Viral); 0 (Ubiquitin); 0 (Viral Envelope Proteins); 157184-61-7 (glycoprotein E2, Hepatitis C virus); EC 2.3.2.26 (UBE3A protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160416
[St] Status:MEDLINE


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[PMID]:27050234
[Au] Autor:Howles SA; Hannan FM; Babinsky VN; Rogers A; Gorvin CM; Rust N; Richardson T; McKenna MJ; Nesbit MA; Thakker RV
[Ad] Endereço:University of Oxford Oxford, United Kingdom.
[Ti] Título:Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations.
[So] Source:N Engl J Med;374(14):1396-1398, 2016 Apr 07.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Calcimiméticos/uso terapêutico
Cloridrato de Cinacalcete/uso terapêutico
Hipercalcemia/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Feminino
Seres Humanos
Hipercalcemia/genética
Masculino
Meia-Idade
Mutação
[Pt] Tipo de publicação:CASE REPORTS; LETTER; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (Calcimimetic Agents); 1K860WSG25 (Cinacalcet Hydrochloride)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160407
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1511646


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[PMID]:26963950
[Au] Autor:Vargas-Poussou R; Mansour-Hendili L; Baron S; Bertocchio JP; Travers C; Simian C; Treard C; Baudouin V; Beltran S; Broux F; Camard O; Cloarec S; Cormier C; Debussche X; Dubosclard E; Eid C; Haymann JP; Kiando SR; Kuhn JM; Lefort G; Linglart A; Lucas-Pouliquen B; Macher MA; Maruani G; Ouzounian S; Polak M; Requeda E; Robier D; Silve C; Souberbielle JC; Tack I; Vezzosi D; Jeunemaitre X; Houillier P
[Ad] Endereço:Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou (R.V.-P., L.M.-H., C.Tra., C.Sim., C.Tre., X.J.), Service de Génétique, Paris, France; INSERM, UMR970 (R.V.-P., L.M.-H., C.Tre., S.R.K., X.J.), Paris-Centre de Recherche Cardiovasculaire, Paris, France; Centre de Référence des
[Ti] Título:Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences.
[So] Source:J Clin Endocrinol Metab;101(5):2185-95, 2016 May.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. OBJECTIVE: This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. DESIGN, SETTING, AND PATIENTS: This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. RESULTS: In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. CONCLUSION: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Hipercalcemia/congênito
Hiperparatireoidismo Primário/genética
Receptores de Detecção de Cálcio/genética
[Mh] Termos MeSH secundário: Adulto
Cálcio/sangue
Estudos Transversais
Análise Mutacional de DNA
Feminino
Genótipo
Seres Humanos
Hipercalcemia/sangue
Hipercalcemia/genética
Hiperparatireoidismo Primário/sangue
Masculino
Meia-Idade
Mutação
Hormônio Paratireóideo/sangue
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (GNA11 protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Parathyroid Hormone); 0 (Receptors, Calcium-Sensing); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160311
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2015-3442


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[PMID]:26920756
[Au] Autor:Choudhury SD; Mushtaq Z; Reddy-Alla S; Balakrishnan SS; Thakur RS; Krishnan KS; Raghu P; Ramaswami M; Kumar V
[Ad] Endereço:Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Govindpura-Bhopal 462 023, Madhya Pradesh, India.
[Ti] Título:σ2-Adaptin Facilitates Basal Synaptic Transmission and Is Required for Regenerating Endo-Exo Cycling Pool Under High-Frequency Nerve Stimulation in Drosophila.
[So] Source:Genetics;203(1):369-85, 2016 May.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The functional requirement of adapter protein 2 (AP2) complex in synaptic membrane retrieval by clathrin-mediated endocytosis is not fully understood. Here we isolated and functionally characterized a mutation that dramatically altered synaptic development. Based on the aberrant neuromuscular junction (NMJ) synapse, we named this mutation angur (a Hindi word meaning "grapes"). Loss-of-function alleles of angur show more than twofold overgrowth in bouton numbers and a dramatic decrease in bouton size. We mapped the angur mutation to σ2-adaptin, the smallest subunit of the AP2 complex. Reducing the neuronal level of any of the subunits of the AP2 complex or disrupting AP2 complex assembly in neurons phenocopied the σ2-adaptin mutation. Genetic perturbation of σ2-adaptin in neurons leads to a reversible temperature-sensitive paralysis at 38°. Electrophysiological analysis of the mutants revealed reduced evoked junction potentials and quantal content. Interestingly, high-frequency nerve stimulation caused prolonged synaptic fatigue at the NMJs. The synaptic levels of subunits of the AP2 complex and clathrin, but not other endocytic proteins, were reduced in the mutants. Moreover, bone morphogenetic protein (BMP)/transforming growth factor ß (TGFß) signaling was altered in these mutants and was restored by normalizing σ2-adaptin in neurons. Thus, our data suggest that (1) while σ2-adaptin facilitates synaptic vesicle (SV) recycling for basal synaptic transmission, its activity is also required for regenerating SVs during high-frequency nerve stimulation, and (2) σ2-adaptin regulates NMJ morphology by attenuating TGFß signaling.
[Mh] Termos MeSH primário: Subunidades sigma do Complexo de Proteínas Adaptadoras/metabolismo
Proteínas de Drosophila/metabolismo
Drosophila/metabolismo
Junção Neuromuscular/metabolismo
Transmissão Sináptica
[Mh] Termos MeSH secundário: Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Animais
Proteínas Morfogenéticas Ósseas/metabolismo
Clatrina/metabolismo
Drosophila/genética
Drosophila/fisiologia
Proteínas de Drosophila/genética
Potenciais Evocados
Mutação
Junção Neuromuscular/fisiologia
Transdução de Sinais
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex sigma Subunits); 0 (Bone Morphogenetic Proteins); 0 (Clathrin); 0 (Drosophila Proteins); 0 (Transforming Growth Factor beta)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170504
[Lr] Data última revisão:
170504
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160228
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.115.183863


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[PMID]:26646938
[Au] Autor:Mayr B; Schnabel D; Dörr HG; Schöfl C
[Ad] Endereço:Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, GermanyCenter for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité University Medicine Berlin, Berlin, Germ
[Ti] Título:GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts.
[So] Source:Eur J Endocrinol;174(5):R189-208, 2016 May.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Hipercalcemia/tratamento farmacológico
Hiperparatireoidismo/tratamento farmacológico
Hipocalcemia/tratamento farmacológico
Receptores de Detecção de Cálcio/genética
[Mh] Termos MeSH secundário: Seres Humanos
Hipercalcemia/genética
Hiperparatireoidismo/genética
Hipocalcemia/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (CASR protein, human); 0 (GNA11 protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Receptors, Calcium-Sensing)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:161018
[Lr] Data última revisão:
161018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151210
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-15-1028


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[PMID]:26082470
[Au] Autor:Hannan FM; Howles SA; Rogers A; Cranston T; Gorvin CM; Babinsky VN; Reed AA; Thakker CE; Bockenhauer D; Brown RS; Connell JM; Cook J; Darzy K; Ehtisham S; Graham U; Hulse T; Hunter SJ; Izatt L; Kumar D; McKenna MJ; McKnight JA; Morrison PJ; Mughal MZ; O'Halloran D; Pearce SH; Porteous ME; Rahman M; Richardson T; Robinson R; Scheers I; Siddique H; Van't Hoff WG; Wang T; Whyte MP; Nesbit MA; Thakker RV
[Ad] Endereço:Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
[Ti] Título:Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.
[So] Source:Hum Mol Genet;24(18):5079-92, 2015 Sep 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Códon
Genes Dominantes
Estudos de Associação Genética
Hipercalcemia/congênito
Mutação
[Mh] Termos MeSH secundário: Complexo 2 de Proteínas Adaptadoras/química
Subunidades sigma do Complexo de Proteínas Adaptadoras/química
Adolescente
Adulto
Substituição de Aminoácidos
Biomarcadores
Linhagem Celular
Criança
Pré-Escolar
Diagnóstico Diferencial
Feminino
Expressão Gênica
Seres Humanos
Hipercalcemia/diagnóstico
Hipercalcemia/genética
Lactente
Masculino
Meia-Idade
Modelos Moleculares
Linhagem
Fenótipo
Conformação Proteica
Relação Estrutura-Atividade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (Biomarkers); 0 (Codon)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150618
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddv226


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[PMID]:25993639
[Au] Autor:Tenhola S; Hendy GN; Valta H; Canaff L; Lee BS; Wong BY; Välimäki MJ; Cole DE; Mäkitie O
[Ad] Endereço:Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Resea
[Ti] Título:Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation.
[So] Source:J Clin Endocrinol Metab;100(7):2515-8, 2015 Jul.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CONTEXT: The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS. CASE DESCRIPTION: Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. CONCLUSIONS: Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Síndrome de DiGeorge/tratamento farmacológico
Hipercalcemia/congênito
Mutação de Sentido Incorreto
Naftalenos/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Sequência de Bases
Cloridrato de Cinacalcete
Síndrome de DiGeorge/complicações
Seres Humanos
Hipercalcemia/complicações
Hipercalcemia/tratamento farmacológico
Hipercalcemia/genética
Masculino
Linhagem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (Naphthalenes); 1K860WSG25 (Cinacalcet Hydrochloride)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150521
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2015-1518


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[PMID]:25378584
[Au] Autor:Jain S; Farías GG; Bonifacino JS
[Ad] Endereço:Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
[Ti] Título:Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1.
[So] Source:Mol Biol Cell;26(2):218-28, 2015 Jan 15.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu(2+) transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the σ1 subunit of the clathrin adaptor AP-1. Under basal Cu(2+) conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative σ1 mutant resulted in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Furthermore, addition of high Cu(2+) concentrations, previously shown to reduce ATP7B incorporation into AP-1-containing clathrin-coated vesicles, caused loss of TGN localization and somatodendritic polarity of ATP7B. These findings support the notion of AP-1 as an effector of polarized sorting in neurons and suggest that altered polarity of ATP7B in polarized cell types might contribute to abnormal copper metabolism in the MEDNIK syndrome, a neurocutaneous disorder caused by mutations in the σ1A subunit isoform of AP-1.
[Mh] Termos MeSH primário: Complexo 1 de Proteínas Adaptadoras/metabolismo
Adenosina Trifosfatases/metabolismo
Proteínas de Transporte de Cátions/metabolismo
Leucina/metabolismo
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Complexo 1 de Proteínas Adaptadoras/química
Complexo 1 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/química
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/metabolismo
Adenosina Trifosfatases/química
Adenosina Trifosfatases/genética
Motivos de Aminoácidos/genética
Sequência de Aminoácidos
Animais
Proteínas de Transporte de Cátions/química
Proteínas de Transporte de Cátions/genética
Membrana Celular/metabolismo
Polaridade Celular
Células Cultivadas
Cobre/metabolismo
Cobre/farmacologia
ATPases Transportadoras de Cobre
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HeLa
Seres Humanos
Leucina/química
Leucina/genética
Microscopia Confocal
Modelos Moleculares
Dados de Sequência Molecular
Mutação
Neurônios/efeitos dos fármacos
Ligação Proteica
Estrutura Terciária de Proteína
Transporte Proteico/efeitos dos fármacos
Proteínas R-SNARE/química
Proteínas R-SNARE/genética
Proteínas R-SNARE/metabolismo
Ratos
Rede trans-Golgi/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (Adaptor Protein Complex 1); 0 (Adaptor Protein Complex sigma Subunits); 0 (Cation Transport Proteins); 0 (R-SNARE Proteins); 0 (VAMP4 protein, rat); 147336-22-9 (Green Fluorescent Proteins); 789U1901C5 (Copper); EC 3.6.1.- (Adenosine Triphosphatases); EC 3.6.3.54 (Atp7b protein, rat); EC 3.6.3.54 (Copper-transporting ATPases); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141108
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E14-07-1177



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