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1.
J Endocr Soc ; 6(3): bvac006, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35178492

RESUMO

CONTEXT: Single-nucleotide polymorphisms (SNPs) in ZBTB38 have been associated with idiopathic short stature (ISS) and adult height. OBJECTIVE: This study sought to (a) characterize the phenotype of ISS patients and their response to recombinant human growth hormone (rhGH) by ZBTB38 SNP genotype; (b) describe the relationship of ZBTB38 expression with normal growth; and (c) describe the in vitro effects of ZBTB38 knockdown on cell proliferation and MCM10 expression. METHODS: The genotype-phenotype relationship of rs6764769 and rs724016 were explored in 261 ISS patients and effects of genotype on response to rhGH were assessed in 93 patients treated with rhGH. The relationship between age and ZBTB38 expression was assessed in 87 normal children and young adults. Knockdown of ZBTB38 in SiHA cells was achieved with siRNAs and cell proliferation assessed with a WST-8 assay. RESULTS: We found that rs6764769 and rs724016 are in linkage disequilibrium. The rs724016 GG genotype was associated with lower birth length (P = 0.01) and a lower change in height SDS over the first year of treatment (P = 0.02). ZBTB38 expression was positively correlated with age (P < 0.001). siRNA-mediated knockdown of ZBTB38 resulted in increased cell proliferation at 72 and 96 hours posttransfection but did not alter expression of MCM10. CONCLUSIONS: SNPs within ZBTB38 associated with ISS are linked to higher birth size within a cohort of ISS patients and a better response to rhGH therapy while ZBTB38 expression is positively related to age.

2.
JCI Insight ; 3(7)2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29618660

RESUMO

BACKGROUND: The effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis. METHODS: Prepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets. Whole blood gene expression was correlated with peak growth hormone (GH) using rank regression and a random forest algorithm tested for prediction of the presence of GHD and in classification of GHD as severe (peak GH <4 µg/l) and nonsevere (peak ≥4 µg/l). Performance was assessed using area under the receiver operating characteristic curve (AUC-ROC). RESULTS: Rank regression identified 347 probe sets in which gene expression correlated with peak GH concentrations (r = ± 0.28, P < 0.01). These 347 probe sets yielded an AUC-ROC of 0.95 for prediction of GHD status versus controls and an AUC-ROC of 0.93 for prediction of GHD severity. CONCLUSION: This study demonstrates highly accurate diagnosis and disease classification for GHD using a combination of transcriptomics and random forest analysis. TRIAL REGISTRATION: NCT00256126 and NCT00699855. FUNDING: Merck and the National Institute for Health Research (CL-2012-06-005).


Assuntos
Perfilação da Expressão Gênica , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/deficiência , Aprendizado de Máquina , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Feminino , Redes Reguladoras de Genes , Transtornos do Crescimento/sangue , Transtornos do Crescimento/genética , Voluntários Saudáveis , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Análise de Componente Principal , Curva ROC , Índice de Gravidade de Doença , Transcriptoma/genética
3.
Lancet Diabetes Endocrinol ; 6(7): 564-574, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29397377

RESUMO

Short stature is a common presentation to paediatric endocrinologists. After exclusion of major endocrine or systemic disease, most children with short stature are diagnosed based on a description of their growth pattern and the height of their parents (eg, familial short stature). Height is a polygenic trait and genome-wide association studies have identified many of the associated genetic loci. Here we review the application of genetic studies, including copy number variant analysis, targeted gene panels, and whole-exome sequencing in children with idiopathic short stature. We estimate 25-40% of children diagnosed with idiopathic short stature could receive a molecular diagnosis using these technologies. A molecular diagnosis for short stature is important for affected individuals and their families and might inform treatment decisions surrounding use of growth hormone or insulin-like growth factor 1 therapy.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Criança , Dosagem de Genes , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Mutação , Sequenciamento do Exoma
4.
Nat Rev Endocrinol ; 13(2): 105-124, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27585961

RESUMO

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.


Assuntos
Gerenciamento Clínico , Internacionalidade , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/terapia , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Síndrome de Silver-Russell/metabolismo
5.
J Clin Endocrinol Metab ; 101(12): 4521-4531, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27525530

RESUMO

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.


Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Receptores da Tireotropina/genética , Tireoglobulina/genética , Humanos , Mutação , Linhagem , Fenótipo
6.
Eur J Pediatr ; 175(7): 967-76, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27169546

RESUMO

UNLABELLED: The diagnosis and management of paediatric Cushing syndrome (CS) is highly challenging. This study aims to characterise its presentation, diagnosis, management and outcome by a retrospective case review of 30 patients (14 females) followed at a single tertiary paediatric endocrinology centre over a 30-year period. At presentation, median age was 8.9 years (0.2-15.5) and the commonest manifestations were weight gain (23/30), hirsutism (17/30), acne (15/30) and hypertension (15/30). Growth retardation was present in 11/30. Median body mass index (BMI) was +2.1 standard deviation score (SDS) (-6.5 to +4.6). Urinary free cortisol (UFC) was abnormal in 17/18 (94 %), midnight cortisol in 27/27 (100 %) and low-dose dexamethasone suppression (LDDS) test in 20/20 (100 %). High-dose dexamethasone suppression (HDDS) test was abnormal in 6/6 (100 %) of adrenal tumours, 1/10 (10 %) of Cushing disease (CD) and 1/2 (50 %) of ectopic tumours. Bilateral inferior petrosal sinus sampling (IPSS) identified five CD cases and one ectopic tumour. All patients underwent surgery and subsequently required cortisol replacement. Final diagnoses were 16 CD, 11 adrenal disease, 2 ectopic ACTH-secreting lesions and 1 case of unidentified aetiology. One year post-diagnosis, median BMI was 0.5 SDS (-2.5 to +3.7), hypertension was present in 4/14 (28 %), and 43 % (12/30) of individuals were off hydrocortisone. CONCLUSION: The prevalence of the clinical manifestations differs from that reported in other series. Screening tests were highly sensitive, with UFC, midnight cortisol and LDDS performing well. One year post-treatment, BMI and BP normalised in the majority of patients and almost half of them were able to discontinue replacement hydrocortisone. WHAT IS KNOWN: •Cushing syndrome is an extremely rare entity in the paediatric and adolescent age groups, so not many cohort studies have been published in this population. •Several tests can be employed to firstly diagnose hypercortisolaemia and secondly identify the source of origin of it. The efficacy and safety of these tests in children is still uncertain. What is New: •This study includes cases due to the different aetiologies of endogenous hypercortisolaemia (pituitary, adrenal and ectopic hypercortisolaemia) allowing us to compare the differences in presentation, diagnosis, management and long-term outcome between the groups. •There is a difference in the prevalence of Cushing syndrome symptoms and in the performance of the tests in our cohort compared to previously published studies in the literature.


Assuntos
Síndrome de Cushing/diagnóstico , Glucocorticoides/uso terapêutico , Adolescente , Criança , Pré-Escolar , Síndrome de Cushing/terapia , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Retrospectivos
7.
Pediatr Res ; 80(2): 299-305, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27057740

RESUMO

BACKGROUND: Later life metabolic dysfunction is a well-recognized consequence of being born small for gestational age (SGA). This study has applied metabolomics to identify whether there are changes in these pathways in prepubertal short SGA children and aimed to compare the intracellular and extracellular metabolome in fibroblasts derived from healthy children and SGA children with postnatal growth impairment. METHODS: Skin fibroblast cell lines were established from eight SGA children (age 1.8-10.3 y) with failure of catch-up growth and from three healthy control children. Confluent cells were incubated in serum-free media and the spent growth medium (metabolic footprint), and intracellular metabolome (metabolic fingerprint) were analyzed by gas-chromatography mass spectrometry. RESULTS: Nineteen metabolites were significantly altered between SGA and control cell lines. The greatest fold difference (FD) was seen for alanine (fingerprint FD, SGA: control 0.3, P = 0.01 and footprint FD = 0.19, P = 0.01), aspartic acid (fingerprint FD = 5.21, P = 0.01), and cystine (footprint FD = 1.66, P = 0.02). Network analysis of the differentially expressed metabolites predicted inhibition of insulin as well as growth (ERK) signaling in SGA cells. CONCLUSION: This study indicates that changes in cellular metabolism associated with both growth failure and insulin insensitivity are present in prepubertal short children born SGA.


Assuntos
Aminoácidos/metabolismo , Glicólise , Transtornos do Crescimento/sangue , Recém-Nascido Pequeno para a Idade Gestacional , Alanina/metabolismo , Ácido Aspártico/metabolismo , Estatura , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Idade Gestacional , Transtornos do Crescimento/complicações , Homozigoto , Humanos , Lactente , Insulina/metabolismo , Resistência à Insulina , Masculino , Metaboloma , Metabolômica , Mutação , Pele/metabolismo
8.
J Med Genet ; 53(9): 634-41, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27091925

RESUMO

BACKGROUND: Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. METHODS: Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. RESULTS: We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (<9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T>C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. CONCLUSIONS: Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.


Assuntos
Nanismo/genética , Complexo I de Transporte de Elétrons/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação/genética , Criança , Pré-Escolar , Exoma/genética , Fácies , Feminino , Estudos de Associação Genética/métodos , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Fenótipo
9.
J Mol Endocrinol ; 52(3): 333-44, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24711643

RESUMO

Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.


Assuntos
Antígenos CD/genética , Proteínas de Transporte/genética , Proteínas Culina/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Hipotonia Muscular/genética , Receptor de Insulina/genética , Coluna Vertebral/anormalidades , Processamento Alternativo/genética , Proteínas de Transporte/biossíntese , Linhagem Celular Tumoral , Proteínas Culina/biossíntese , Proteínas do Citoesqueleto/biossíntese , Fibroblastos , Perfilação da Expressão Gênica , Transtornos do Crescimento/genética , Células HEK293 , Hormônio do Crescimento Humano/genética , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/deficiência , Fator de Crescimento Insulin-Like II/genética , Proteína Supressora de Tumor p53/genética , Ubiquitinação/genética
10.
Am J Med Genet C Semin Med Genet ; 163C(2): 76-85, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23613426

RESUMO

Human growth is a complex process starting at conception and completing in adolescence at the time of growth plate fusion. Growth can be divided into four phases: (1) fetal, where the predominant endocrine factors controlling growth are insulin and the insulin-like growth factors. (2) Infancy, where growth is mainly dependent upon nutrition. (3) Childhood, where the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis and thyroid hormone are most important. (4) Puberty, where along with the GH-IGF-I axis the activation of the hypothalamo-pituitary-gonadal axis to generate sex steroid secretion becomes vital to the completion of growth. GH is released from the pituitary in a pulsatile fashion under the control of GHRH, Ghrelin, and somatostatin and, via a complex signal transduction cascade, initiates the release of IGF-I within many tissues but predominantly the liver and at the growth plate. IGF-I acts in an autocrine and paracrine manner via the IGF-I receptor to stimulate cell proliferation and longitudinal growth. Activation of the pituitary-gonadal axis during puberty occurs via a complex interaction of factors including kisspeptin, leptin, gonadotrophin releasing hormone, and tachykinin ultimately leading to augmentation of GH secretion, the pubertal growth spurt, and fusion of the growth plates. Many other hormones can affect the GH-IGF-I system or directly affect cell proliferation at the growth plate including thyroid hormone, vitamin D, and corticosteroids.


Assuntos
Glândulas Endócrinas/fisiologia , Crescimento/fisiologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Puberdade
11.
Clin Endocrinol (Oxf) ; 77(3): 335-42, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22624670

RESUMO

3-M syndrome is an autosomal recessive primordial growth disorder characterized by small birth size and post-natal growth restriction associated with a spectrum of minor anomalies (including a triangular-shaped face, flat cheeks, full lips, short chest and prominent fleshy heels). Unlike many other primordial short stature syndromes, intelligence is normal and there is no other major system involvement, indicating that 3-M is predominantly a growth-related condition. From an endocrine perspective, serum GH levels are usually normal and IGF-I normal or low, while growth response to rhGH therapy is variable but typically poor. All these features suggest a degree of resistance in the GH-IGF axis. To date, mutations in three genes CUL7, OBSL1 and CCDC8 have been shown to cause 3-M. CUL7 acts an ubiquitin ligase and is known to interact with p53, cyclin D-1 and the growth factor signalling molecule IRS-1, the link with the latter may contribute to the GH-IGF resistance. OBSL1 is a putative cytoskeletal adaptor that interacts with and stabilizes CUL7. CCDC8 is the newest member of the pathway and interacts with OBSL1 and, like CUL7, associates with p53, acting as a co-factor in p53-medicated apoptosis. 3-M patients without a mutation have also been identified, indicating the involvement of additional genes in the pathway. Potentially damaging sequence variants in CUL7 and OBSL1 have been identified in idiopathic short stature (ISS), including those born small with failure of catch-up growth, signifying that the 3-M pathway could play a wider role in disordered growth.


Assuntos
Nanismo/diagnóstico , Hipotonia Muscular/diagnóstico , Proteínas de Transporte/genética , Criança , Proteínas Culina/genética , Proteínas do Citoesqueleto/genética , Diagnóstico Diferencial , Nanismo/tratamento farmacológico , Nanismo/genética , Nanismo/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Redes e Vias Metabólicas , Hipotonia Muscular/tratamento farmacológico , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Mutação , Gravidez , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Coluna Vertebral/anormalidades , Coluna Vertebral/metabolismo , Ubiquitinação
12.
Horm Res Paediatr ; 76(6): 369-78, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22156540

RESUMO

3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth.


Assuntos
Desenvolvimento do Adolescente , Proteínas de Transporte/metabolismo , Desenvolvimento Infantil , Proteínas Culina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Nanismo/genética , Nanismo/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Adolescente , Animais , Estatura , Proteínas de Transporte/genética , Criança , Proteínas Culina/genética , Proteínas do Citoesqueleto/genética , Nanismo/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Hipotonia Muscular/fisiopatologia , Proteínas Mutantes/metabolismo , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo , Síndrome de Silver-Russell/fisiopatologia , Coluna Vertebral/anormalidades , Coluna Vertebral/metabolismo , Coluna Vertebral/fisiopatologia
13.
Am J Hum Genet ; 89(1): 148-53, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21737058

RESUMO

3-M syndrome, a primordial growth disorder, is associated with mutations in CUL7 and OBSL1. Exome sequencing now identifies mutations in CCDC8 as a cause of 3-M syndrome. CCDC8 is a widely expressed gene that is transcriptionally associated to CUL7 and OBSL1, and coimmunoprecipitation indicates a physical interaction between CCDC8 and OBSL1 but not CUL7. We propose that CUL7, OBSL1, and CCDC8 are members of a pathway controlling mammalian growth.


Assuntos
Proteínas Culina/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Linhagem Celular , Pré-Escolar , Proteínas Culina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Feminino , Expressão Gênica , Homozigoto , Humanos , Lactente , Masculino , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Coluna Vertebral/anormalidades , Fatores de Transcrição
14.
Nat Rev Endocrinol ; 7(1): 11-24, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20956999

RESUMO

Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.


Assuntos
Hormônio do Crescimento/metabolismo , Insulina/metabolismo , Neoplasias/metabolismo , Somatomedinas/metabolismo , Animais , Humanos , Camundongos , Neoplasias/epidemiologia , Neoplasias/genética
15.
Am J Hum Genet ; 84(6): 801-6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19481195

RESUMO

3-M syndrome is an autosomal-recessive primordial growth disorder characterized by significant intrauterine and postnatal growth restriction. Mutations in the CUL7 gene are known to cause 3-M syndrome. In 3-M syndrome patients that do not carry CUL7 mutations, we performed high-density genome-wide SNP mapping to identify a second locus at 2q35-q36.1. Further haplotype analysis revealed a 1.29 Mb interval in which the underlying gene is located and we subsequently discovered seven distinct null mutations from 10 families within the gene OBSL1. OBSL1 is a putative cytoskeletal adaptor protein that localizes to the nuclear envelope. We were also able to demonstrate that loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels and suggesting that both proteins are involved within the same molecular pathway.


Assuntos
Proteínas do Citoesqueleto/genética , Transtornos do Crescimento/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Ubiquitinação , Adolescente , Células Cultivadas , Criança , Pré-Escolar , Proteínas Culina/genética , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto , Feminino , Humanos , Lactente , Rim/citologia , Rim/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , RNA Interferente Pequeno/farmacologia , Síndrome
16.
Pediatrics ; 121(4): e754-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18346987

RESUMO

OBJECTIVE: Although nasal continuous positive airway pressure is widely used in neonatal units, its use in neonatal transport is not yet established. Previous reports have been limited to small numbers of primary road transports and larger numbers of return transports while its use in air transportation has not been reported. The aim of this study was to assess the safety and effectiveness of transporting neonates and infants by road or air while treated with nasal continuous positive airway pressure. METHODS: We conducted a retrospective review of the records of all infants transported between January 1, 2004, and November 1, 2005. RESULTS: A total of 220 infants were treated with nasal continuous positive airway pressure; of these, 13 infants (6%) were intubated before transport, leaving 207 infants transported on a median nasal continuous positive airway pressure of 7 cm H(2)O. Thirty infants were transported by fixed or rotary wing aircraft and 190 by road. No infants required intubation or bag and mask ventilation during transport. Twenty-eight infants (13%) required intubation within 24 hours of arrival at the receiving hospital, 4 infants (2%) were intubated > 24 hours after arrival, 11 infants (5%) were intubated for surgery, and 164 infants (73%) were never intubated. A total of 111 infants (50%) were preterm and < 72 hours old at transport, and 32 infants (15%) were < or = 32 weeks' gestational age and < 72 hours old at transport. Fraction of inspired oxygen was significantly lower at the end of transport (0.45 vs 0.34). CONCLUSIONS: Nasal continuous positive airway pressure is effective and has an acceptable safety margin for the road-based transportation of infants with acute respiratory distress. Air transport is feasible but larger studies are required to assess safety.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Recém-Nascido Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Transporte de Pacientes/métodos , Gasometria , Estudos de Coortes , Intervalos de Confiança , Feminino , Seguimentos , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Probabilidade , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/mortalidade , Estudos Retrospectivos , Medição de Risco , Segurança , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do Tratamento , Desmame do Respirador
17.
J Pediatr Endocrinol Metab ; 18(5): 471-6, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15921176

RESUMO

AIM: To determine whether patients with septooptic dysplasia (SOD) are of normal birth weight and gestation but are born to mothers who are significantly younger than average. METHODS: Retrospective study of 30 patients with SOD attending the Royal Hospital for Sick Children, Glasgow. Birth data for the Scottish population were used for comparison. RESULTS: Mean birth weight was 3.42 (range 2.66-4.18) kg. One patient was born preterm while the rest were born at term. Data for the Scottish population were available from 1979 onwards and 26 patients born after this year were selected for analysis. Median maternal age in this group was 21 (range 16-41) years, significantly lower than the median maternal age for Scotland of 27.12 (range 25.8-28.6) years (95% CI 4.8-8.0 years). CONCLUSION: Patients with SOD are of normal birth weight and gestation but are born to mothers who are significantly younger than average.


Assuntos
Idade Materna , Displasia Septo-Óptica/epidemiologia , Displasia Septo-Óptica/etiologia , Adolescente , Adulto , Distribuição por Idade , Peso ao Nascer , Parto Obstétrico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Estudos Retrospectivos , Fatores de Risco , Escócia/epidemiologia , População Branca
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