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2.
Endocr Connect ; 8(5): 468-480, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30921766

RESUMO

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare disease with a wide spectrum of reproductive and non-reproductive clinical characteristics. Apart from the phenotypic heterogeneity, IGD is also highly genetically heterogeneous with >35 genes implicated in the disease. Despite this genetic heterogeneity, genetic enrichment in specific subpopulations has been described. We have previously described low prevalence of genetic variation in the Greek IGD cohort discovered with utilization of Sanger sequencing in 14 known IGD genes. Here, we describe the expansion of genetic screening in the largest IGD Greek cohort that has ever been studied with the usage of whole-exome sequencing, searching for rare sequencing variants (RSVs) in 37 known IGD genes. Even though Sanger sequencing detected genetic variation in 21/81 IGD patients in 7/14 IGD genes without any evidence of oligogenicity, whole exome sequencing (WES) revealed that 27/87 IGD patients carried a rare genetic change in a total of 15 genes with 4 IGD cases being oligogenic. Our findings suggest that next-generation sequencing (NGS) techniques can discover previously undetected variation, making them the standardized method for screening patients with rare and/or more common disorders.

5.
Endocr Rev ; 2016(1): 4-22, 2016 02.
Artigo em Inglês | MEDLINE | ID: mdl-27454361

RESUMO

The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015).


Assuntos
Variação Genética , Genômica/métodos , Hipotálamo/fisiopatologia , Reprodução , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hipogonadismo/fisiopatologia , Hipotálamo/metabolismo , Masculino
6.
Endocr Rev ; 36(6): 603-21, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26394276

RESUMO

The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3) substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.


Assuntos
Hormônio Liberador de Gonadotropina/deficiência , Hormônio Liberador de Gonadotropina/genética , Hipotálamo/fisiologia , Reprodução/genética , Cariótipo Anormal , Deleção de Genes , Hormônio Liberador de Gonadotropina/fisiologia , Humanos , Sistema Nervoso/crescimento & desenvolvimento , Neurônios/fisiologia , Sistemas Neurossecretores/fisiologia , Linhagem , Fenótipo , Síndrome
7.
Hippokratia ; 13(2): 125-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19561787

RESUMO

Prader-Willi syndrome (PWS) is a neurobehavioral disorder characterized mainly by neonatal hypotonia, dysmorphic features, hypogonadism, mental retardation and behavioral problems. The PWS has not been associated with renal complications. We report the case of an infant with Prader-Willi syndrome due to loss of the paternal copy of chromosome 15q11.2-13, who presented with severe proteinuria and microscopic hematuria. Renal biopsy revealed mesangioproliferative glomerulonephritis (MPGN). The early onset of the primary MPGN in this infant make us consider a possible association between the deficiency of the paternally expressed genes from the 15q11-q13 region and the renal disease.

8.
Ann Nutr Metab ; 51(5): 471-6, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18025822

RESUMO

BACKGROUND AND AIMS: Pediatric hypertension is urgently increasing in Greece. The purpose of this study is to record the prevalence of hypertension in schoolchildren and to relate dietary minerals to blood pressure (BP). METHODS AND RESULTS: 308 males and 298 females, aged 7-15 years, from 10 schools in Northern Greece participated in the study. BP and dietary minerals were measured in all children. Twenty-seven and 12.3% of boys and 21.2 and 15.1% of girls were diagnosed with prehypertension systolic BP and systolic hypertension, respectively. For diastolic BP, 19 and 13.3% of boys and 21.5 and 15.1% of girls were diagnosed with prehypertension diastolic BP and diastolic hypertension, respectively. Systolic BP was significantly positively associated with age (beta: 0.283, 95% CI: 1.440-2.484, p < 0.001), BMI (beta: 0.267, 95% CI: 0.830-1.489, p < 0.001) and potassium (beta: 0.139, 95% CI: 0.001-0.005, p < 0.001) and negatively related to Ca (beta: -0.160, 95% CI: -0.012 to 0.002, p = 0.007). Diastolic BP was positively related only to BMI (beta: 0.194, 95% CI: 0.380-0.968, p < 0.001). CONCLUSION: The current study tried to estimate the prevalence of hypertension among children in Northern Greece. Early prevention through nutrition education programs on BP that include diet and exercise modifications is urgently needed in order to avoid certain chronic risk factors in early life.


Assuntos
Hipertensão/sangue , Hipertensão/epidemiologia , Minerais/administração & dosagem , Minerais/sangue , Obesidade/epidemiologia , Adolescente , Fenômenos Fisiológicos da Nutrição do Adolescente/fisiologia , Envelhecimento/sangue , Envelhecimento/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Cálcio/sangue , Criança , Fenômenos Fisiológicos da Nutrição Infantil/fisiologia , Doença Crônica , Feminino , Grécia/epidemiologia , Humanos , Hipertensão/etiologia , Masculino , Obesidade/complicações , Potássio/sangue , Prevalência , Fatores de Risco
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