Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650157

RESUMO

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.


Assuntos
Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Neurossecreção/fisiologia , Somatotrofos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Hormônio do Crescimento/biossíntese , Humanos , Imunoglobulinas/deficiência , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Pessoa de Meia-Idade
3.
Clin Endocrinol (Oxf) ; 89(6): 813-823, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30086211

RESUMO

OBJECTIVE: Loss-of-function mutations in IGSF1 result in X-linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred. DESIGN, PATIENTS AND MEASUREMENTS: A novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype-phenotype correlations were investigated in the wider kindred. RESULTS: The mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH-based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75-year-old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed. CONCLUSIONS: As observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi-generation genetic ascertainment in affected families, especially where TSH-based CH screening programmes may fail to detect CeCH at birth.


Assuntos
Hipotireoidismo Congênito/genética , Imunoglobulinas/genética , Proteínas de Membrana/genética , Mutação/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/diagnóstico , Feminino , Humanos , Lactente , Irlanda , Masculino , Pessoa de Meia-Idade , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto Jovem
5.
Nature ; 554(7692): 378-381, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29414946

RESUMO

Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.


Assuntos
Asparagina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metástase Neoplásica/patologia , Animais , Asparaginase/metabolismo , Asparaginase/uso terapêutico , Asparagina/deficiência , Aspartato-Amônia Ligase/genética , Aspartato-Amônia Ligase/metabolismo , Disponibilidade Biológica , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Invasividade Neoplásica/patologia , Prognóstico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Interferência de RNA , Reprodutibilidade dos Testes
6.
Front Oncol ; 8: 15, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29459886

RESUMO

Although there has been a renewed interest in the field of cancer metabolism in the last decade, the link between metabolism and DNA damage/DNA repair in cancer has yet to be appreciably explored. In this review, we examine the evidence connecting DNA damage and repair mechanisms with cell metabolism through three principal links. (1) Regulation of methyl- and acetyl-group donors through different metabolic pathways can impact DNA folding and remodeling, an essential part of accurate double strand break repair. (2) Glutamine, aspartate, and other nutrients are essential for de novo nucleotide synthesis, which dictates the availability of the nucleotide pool, and thereby influences DNA repair and replication. (3) Reactive oxygen species, which can increase oxidative DNA damage and hence the load of the DNA-repair machinery, are regulated through different metabolic pathways. Interestingly, while metabolism affects DNA repair, DNA damage can also induce metabolic rewiring. Activation of the DNA damage response (DDR) triggers an increase in nucleotide synthesis and anabolic glucose metabolism, while also reducing glutamine anaplerosis. Furthermore, mutations in genes involved in the DDR and DNA repair also lead to metabolic rewiring. Links between cancer metabolism and DNA damage/DNA repair are increasingly apparent, yielding opportunities to investigate the mechanistic basis behind potential metabolic vulnerabilities of a substantial fraction of tumors.

7.
Nat Commun ; 8(1): 1865, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192207

RESUMO

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Estradiol/análogos & derivados , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio/genética , Linhagem Celular Tumoral , Estradiol/uso terapêutico , Feminino , Fulvestranto , Humanos , Células MCF-7 , Mutação , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico
8.
J Endocr Soc ; 1(6): 731-736, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29264525

RESUMO

CONTEXT: IGSF1 deficiency is a recently discovered syndrome consisting of congenital central hypothyroidism (CeH) and macroorchidism. Here, we report on a patient presenting with short stature, who was found to carry a pathogenic mutation in the IGSF1 gene. CASE DESCRIPTION: A 14-year-old Israeli boy was referred to the Academic Medical Center in Amsterdam, The Netherlands, for follow-up on short stature ascribed to constitutional delay of growth and puberty, and familial hypercholesterolemia. Primary hypothyroidism had previously been excluded by a normal thyroid-stimulating hormone (TSH) concentration. However, in follow-up, plasma free thyroxine (FT4) concentrations were repeatedly low, and the patient was diagnosed with CeH. Because of coexistent relative macroorchidism, IGSF1 gene analysis was performed, revealing a mutation (c.2588C>G; p.Ser863Cys). The mutant IGSF1 protein was retained mainly in the endoplasmic reticulum and reached the plasma membrane with poor efficiency compared with wild-type protein. After starting thyroxine treatment, plasma cholesterol almost normalized. CONCLUSIONS: This case illustrates the necessity of measuring both FT4 and TSH when hypothyroidism is suspected, or needs to be ruled out. In addition, this case suggests that the presence of childhood hypercholesterolemia may be an indication of undiagnosed hypothyroidism.

9.
Endocrinology ; 158(4): 815-830, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28324000

RESUMO

Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in thyrotropin (TSH)-producing thyrotrope cells of the anterior pituitary gland. The protein is cotranslationally cleaved, with only its C-terminal domain (CTD) being trafficked to the plasma membrane. Most intragenic IGSF1 mutations in humans map to the CTD. In this study, we used CRISPR-Cas9 to introduce a loss-of-function mutation into the IGSF1-CTD in mice. The modified allele encodes a truncated protein that fails to traffic to the plasma membrane. Under standard laboratory conditions, Igsf1-deficient males exhibit normal serum TSH levels as well as normal numbers of TSH-expressing thyrotropes. However, pituitary expression of the TSH subunit genes and TSH protein content are reduced, as is expression of the receptor for thyrotropin-releasing hormone (TRH). When challenged with exogenous TRH, Igsf1-deficient males release TSH, but to a significantly lesser extent than do their wild-type littermates. The mice show similarly attenuated TSH secretion when rendered profoundly hypothyroid with a low iodine diet supplemented with propylthiouracil. Collectively, these results indicate that impairments in pituitary TRH receptor expression and/or downstream signaling underlie central hypothyroidism in IGSF1 deficiency syndrome.


Assuntos
Imunoglobulinas/genética , Proteínas de Membrana/genética , Hipófise/metabolismo , Receptores do Hormônio Liberador da Tireotropina/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Tireotropina/metabolismo , Animais , Imunoglobulinas/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Receptores do Hormônio Liberador da Tireotropina/genética , Transdução de Sinais/fisiologia , Tireotropina/genética , Hormônio Liberador de Tireotropina/genética
10.
Thyroid ; 26(12): 1693-1700, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27310681

RESUMO

BACKGROUND: Congenital hypothyroidism of central origin (CH-C) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin stimulation of a normal thyroid gland. A recently described syndrome of isolated CH-C and macroorchidism was attributed to loss-of-function mutations of the immunoglobulin superfamily, member 1 gene (IGSF1). PATIENTS AND METHODS: CH-C was diagnosed in three siblings. The TRH, TRHR, and TSHB genes were sequenced followed by whole-exome sequencing in the proband. A mutation identified in IGSF1 was analyzed by direct PCR sequencing in family members. The effects of the mutation were assessed by in vitro studies in HEK293 cells. RESULTS: The index case was negative for mutations in TRH, TRHR, and TSHB. Whole-exome sequencing revealed a novel insertion mutation in IGSF1, c.2284_2285insA, p.R762QfsX7, which was confirmed by direct PCR sequencing and was identified in six additional family members. The mutation introduces a frame-shift and premature stop codon in the seventh Ig loop, thereby truncating IGSF1. In vitro studies revealed that the mutated IGSF1-R762QfsX7 migrates as a doublet at ∼28 kDa, which is far smaller than the wild type protein (130-140 kDa). Both bands were endonuclease H sensitive, indicating immature glycosylation and failure of the protein to traffic out of the endoplasmic reticulum to the plasma membrane. Further phenotypic findings in the family included macroorchidism and infertility in the uncle and mild neurological phenotypes in the affected males, such as hypotonia, delayed psychomotor development, clumsy behavior, and attention deficit disorder. CONCLUSIONS: We identified a novel insertion mutation in the IGSF1 gene and further delineated the phenotype of the IGSF1-deficiency syndrome. Our findings indicate a possible association between an IGSF1 mutation and neurological phenotypes.


Assuntos
Hipotireoidismo Congênito/genética , Hipotireoidismo/genética , Imunoglobulinas/genética , Proteínas de Membrana/genética , Pré-Escolar , Análise Mutacional de DNA , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Receptores do Hormônio Liberador da Tireotropina/genética , Irmãos , Tireotropina/genética , Hormônio Liberador de Tireotropina/genética
11.
J Clin Res Pediatr Endocrinol ; 8(1): 86-91, 2016 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-26757742

RESUMO

Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency.


Assuntos
Hipoglicemiantes/uso terapêutico , Adolescente , Adulto , Biomarcadores/análise , Glicemia/análise , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Lactente , Masculino , Prognóstico , Estudos Prospectivos , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...