Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros

Bases de dados
Tipo de documento
Intervalo de ano de publicação
1.
Nucleic Acids Res ; 50(12): 6735-6752, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35713545

RESUMO

We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143 hypervariable CpGs ('hvCpGs') with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for proximity to ERV1 and ERVK retrovirus elements. hvCpGs were also enriched for loci previously associated with periconceptional environment, parent-of-origin-specific methylation, and distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.


Assuntos
Metilação de DNA , Embrião de Mamíferos , Humanos , Metilação de DNA/genética , Reprodutibilidade dos Testes , Embrião de Mamíferos/metabolismo , Ilhas de CpG , Etnicidade
2.
J Med Genet ; 57(10): 683-691, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32054688

RESUMO

BACKGROUND: Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%-10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS. METHODS: A retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped. RESULTS: The median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤-2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS. CONCLUSION: Historical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.


Assuntos
Fator de Crescimento Insulin-Like II/genética , RNA Longo não Codificante/genética , Síndrome de Silver-Russell/genética , Dissomia Uniparental/genética , Adolescente , Adulto , Idoso , Metilação de DNA/genética , Epigênese Genética , Feminino , Impressão Genômica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Qualidade de Vida , Síndrome de Silver-Russell/patologia , Dissomia Uniparental/patologia , Adulto Jovem
3.
PLoS Genet ; 13(1): e1006470, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28081210

RESUMO

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development.


Assuntos
Moléculas de Adesão Celular/genética , Fenda Labial/genética , Fissura Palatina/genética , Coração Triatriado/genética , Hialuronoglucosaminidase/genética , Mutação , Adolescente , Animais , Criança , Pré-Escolar , Fenda Labial/patologia , Fissura Palatina/patologia , Coração Triatriado/patologia , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Penetrância , Síndrome
4.
Am J Hum Genet ; 98(4): 755-62, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27018475

RESUMO

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.


Assuntos
Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Fases de Leitura Aberta , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Estudos de Casos e Controles , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Cistos/diagnóstico , Cistos/genética , Humanos , Lábio/anormalidades , Mutação , Polimorfismo de Nucleotídeo Único , Grupos Raciais/genética
5.
Hum Mutat ; 38(6): 615-620, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28256047

RESUMO

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare cause of pulmonary hypertension in newborns. Maternally inherited point mutations in Forkhead Box F1 gene (FOXF1), deletions of the gene, or its long-range enhancers on the maternal allele are responsible for this neonatal lethal disorder. Here, we describe monozygotic twins and one full-term newborn with ACD and gastrointestinal malformations caused by de novo mutations of FOXF1 on the maternal-inherited alleles. Since this parental transmission is consistent with genomic imprinting, the parent-of-origin specific monoallelic expression of genes, we have undertaken a detailed analysis of both allelic expression and DNA methylation. FOXF1 and its neighboring gene FENDRR were both biallelically expressed in a wide range of fetal tissues, including lung and intestine. Furthermore, detailed methylation screening within the 16q24.1 regions failed to identify regions of allelic methylation, suggesting that disrupted imprinting is not responsible for ACDMPV.


Assuntos
Fatores de Transcrição Forkhead/genética , Impressão Genômica , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Alvéolos Pulmonares/anormalidades , Hibridização Genômica Comparativa , Metilação de DNA/genética , Feminino , Humanos , Hipertensão Pulmonar , Recém-Nascido , Herança Materna/genética , Mutação , Síndrome da Persistência do Padrão de Circulação Fetal/complicações , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Gravidez , Alvéolos Pulmonares/patologia , Gêmeos Monozigóticos
6.
Am J Hum Genet ; 95(5): 611-21, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25439728

RESUMO

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.


Assuntos
Ataxia Cerebelar/genética , Deficiência Intelectual/genética , Nexinas de Classificação/genética , Sequência de Bases , Ataxia Cerebelar/patologia , Mapeamento Cromossômico , Códon sem Sentido/genética , Feminino , Fibroblastos/ultraestrutura , Redes Reguladoras de Genes/genética , Genes Recessivos/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Microscopia Eletrônica , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
7.
Am J Hum Genet ; 90(4): 715-9, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22444668

RESUMO

Birth weight is an important indicator of both perinatal and adult health, but little is known about the genetic factors contributing to its variability. Intrauterine growth restriction is a leading cause of perinatal morbidity and mortality and is also associated with adult disease. A significant correlation has been reported between lower birth weight and increased expression of the maternal PHLDA2 allele in term placenta (the normal imprinting pattern was maintained). However, a mechanism that explains the transcriptional regulation of PHLDA2 on in utero growth has yet to be described. In this study, we sequenced the PHLDA2 promoter region in 263 fetal DNA samples to identify polymorphic variants. We used a luciferase reporter assay to identify in the PHLDA2 promoter a 15 bp repeat sequence (RS1) variant that significantly reduces PHLDA2-promoter efficiency. RS1 genotyping was then performed in three independent white European normal birth cohorts. Meta-analysis of all three (total n = 9,433) showed that maternal inheritance of RS1 resulted in a significant 93 g increase in birth weight (p = 0.01; 95% confidence interval [CI] = 22-163). Moreover, when the mother was homozygous for RS1, the influence on birth weight was 155 g (p = 0.04; 95% CI = 9-300), which is a similar magnitude to the reduction in birth weight caused by maternal smoking.


Assuntos
Peso ao Nascer/genética , Feto/metabolismo , Impressão Genômica , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Adulto , Sequência de Bases , Feminino , Variação Genética , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Dados de Sequência Molecular , Sequências Repetitivas de Ácido Nucleico/genética , População Branca/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-38961758

RESUMO

CONTEXT: Diabetes mellitus (DM) risk factors in Turner Syndrome (TS) may include autoimmunity, obesity, beta-cell dysfunction, genetic predisposition and insulin resistance (IR). OBJECTIVE: Evaluate glucose tolerance and DM risk factors in adults with TS. DESIGN: A single centre study with two phases. To determine the prevalence of DM and to assess diabetes risk markers comparing women with TS with and without impaired glucose tolerance (IGT). SETTING: Tertiary referral center, University College Hospitals. PATIENTS: 106 Women with TS (age range 18-70 years) undergoing annual health surveillance. INTERVENTIONS: Participants underwent oral glucose tolerance tests (OGTT), with additional samples for autoimmunity and genetic analysis. MAIN OUTCOME MEASURE: Glucose tolerance, insulin, autoimmune and single nucleotide polymorphism (SNP) profile. RESULTS: OGTT screening showed that those without a previous DM diagnosis, 72.7% had normal glucose tolerance, 19.5% had IGT, and 7.6% were newly diagnosed with DM. OGTT identified more cases of DM than HbAc1 sampling alone. Women with IGT or DM were older, with higher body mass index and IR. No association was found between autoimmune markers GAD, IA-2 and ZnT8, risk karyotypes or selected SNPs and DM. In DM cases, GAD positivity was associated with requirement for insulin therapy. The median age of onset of the diagnosis of DM was 36 years (range 11-56). CONCLUSIONS: In the spectrum of DM subtypes, TS-associated DM lies between type 1 and type 2 DM with features of both. Key factors include weight and IR. Assessing C-peptide or GAD antibodies may aid future insulin requirement.

9.
J Clin Endocrinol Metab ; 109(10): e1889-e1901, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-38888172

RESUMO

Silver-Russell syndrome (SRS) is a clinical diagnosis requiring the fulfillment of ≥ 4/6 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria. A score of ≥ 4/6 NH-CSS (or ≥ 3/6 with strong clinical suspicion) warrants (epi)genetic confirmation, identifiable in ∼60% patients. The approach to the investigation and diagnosis of SRS is detailed in the only international consensus guidance, published in 2016. In the intervening years, the clinical, biochemical, and (epi)genetic characteristics of SRS have rapidly expanded, largely attributable to advancing molecular genetic techniques and a greater awareness of related disorders. The most common etiologies of SRS remain loss of methylation of chromosome 11p15 (11p15LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). Rarer causes of SRS include monogenic pathogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (PLAG1 and HMGA2) genes. Although the age-specific NH-CSS can identify more common molecular causes of SRS, its use in identifying monogenic causes is unclear. Preliminary data suggest that NH-CSS is poor at identifying many of these cases. Additionally, there has been increased recognition of conditions with phenotypes overlapping with SRS that may fulfill NH-CSS criteria but have distinct genetic etiologies and disease trajectories. This group of conditions is frequently overlooked and under-investigated, leading to no or delayed diagnosis. Like SRS, these conditions are multisystemic disorders requiring multidisciplinary care and tailored management strategies. Early identification is crucial to improve outcomes and reduce the major burden of the diagnostic odyssey for patients and families. This article aims to enable clinicians to identify key features of rarer causes of SRS and conditions with overlapping phenotypes, show a logical approach to the molecular investigation, and highlight the differences in clinical management strategies.


Assuntos
Síndrome de Silver-Russell , Humanos , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/terapia
10.
Nat Commun ; 15(1): 8420, 2024 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-39341815

RESUMO

Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease.


Assuntos
Gastroenteropatias , Transtornos do Crescimento , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/imunologia , Fibroblastos/metabolismo , Gastroenteropatias/genética , Gastroenteropatias/patologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/deficiência , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/genética , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Linhagem , Fosforilação , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição STAT5/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/deficiência , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética
11.
Front Endocrinol (Lausanne) ; 14: 1227164, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37800145

RESUMO

Background: Women with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management. Objective: We investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a "two-hit" hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated. Methods: Whole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA. Results: Standard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p<0.02). Conclusions: Women with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated.


Assuntos
Diabetes Mellitus , Síndrome de Turner , Adulto , Humanos , Feminino , Síndrome de Turner/genética , Cariotipagem , Autoimunidade , Fenótipo
12.
Front Endocrinol (Lausanne) ; 13: 953707, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060959

RESUMO

Background: Heterozygous de novo variants in SAMD9 cause MIRAGE syndrome, a complex multisystem disorder involving Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy. The range of additional clinical associations is expanding and includes disrupted placental development, poor post-natal growth and endocrine features. Increasingly, milder phenotypic features such as hypospadias in small for gestational age (SGA) boys and normal adrenal function are reported. Some children present with isolated myelodysplastic syndrome (MDS/monosomy 7) without MIRAGE features. Objective: We aimed to investigate: 1) the range of reported SAMD9 variants, clinical features, and possible genotype-phenotype correlations; 2) whether SAMD9 disruption affects placental function and leads to pregnancy loss/recurrent miscarriage (RM); 3) and if pathogenic variants are associated with isolated fetal growth restriction (FGR). Methods: Published data were analyzed, particularly reviewing position/type of variant, pregnancy, growth data, and associated endocrine features. Genetic analysis of SAMD9 was performed in products of conception (POC, n=26), RM couples, (couples n=48; individuals n=96), children with FGR (n=44), SGA (n=20), and clinical Silver-Russell Syndrome (SRS, n=8), (total n=194). Results: To date, SAMD9 variants are reported in 116 individuals [MDS/monosomy 7, 64 (55.2%); MIRAGE, 52 (44.8%)]. Children with MIRAGE features are increasingly reported without an adrenal phenotype (11/52, 21.2%). Infants without adrenal dysfunction were heavier at birth (median 1515 g versus 1020 g; P < 0.05) and born later (median 34.5 weeks versus 31.0; P < 0.05) compared to those with adrenal insufficiency. In MIRAGE patients, hypospadias is a common feature. Additional endocrinopathies include hypothyroidism, hypo- and hyper-glycemia, short stature and panhypopituitarism. Despite this increasing range of phenotypes, genetic analysis did not reveal any likely pathogenic variants/enrichment of specific variants in SAMD9 in the pregnancy loss/growth restriction cohorts studied. Conclusion: MIRAGE syndrome is more phenotypically diverse than originally reported and includes growth restriction and multisystem features, but without adrenal insufficiency. Endocrinopathies might be overlooked or develop gradually, and may be underreported. As clinical features including FGR, severe infections, anemia and lung problems can be non-specific and are often seen in neonatal medicine, SAMD9-associated conditions may be underdiagnosed. Reaching a specific diagnosis of MIRAGE syndrome is critical for personalized management.


Assuntos
Insuficiência Adrenal , Hipospadia , Síndromes Mielodisplásicas , Insuficiência Adrenal/complicações , Insuficiência Adrenal/genética , Deleção Cromossômica , Cromossomos Humanos Par 7 , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Hipospadia/complicações , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Fenótipo , Placenta , Gravidez , Síndrome
13.
JCI Insight ; 7(5)2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35138268

RESUMO

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI.


Assuntos
Insuficiência Ovariana Primária , RNA Helicases , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Feminino , Humanos , Meiose , Insuficiência Ovariana Primária/genética , RNA Helicases/genética
14.
Eur J Endocrinol ; 183(6): 581-595, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33055295

RESUMO

OBJECTIVE: Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1). DESIGN AND METHODS: Array comparative genomic hybridisation was performed with ~60 000 probe oligonucleotide array in GHI (n = 53) and IGF-1 insensitivity (n = 10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions. RESULTS: Both cohorts were enriched for class 3-5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n = 2), 12q14 (n = 1) deletions and Xp22 (n = 1), Xq26 (n = 1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts. CONCLUSIONS: Our cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.


Assuntos
Variações do Número de Cópias de DNA/genética , Testes Genéticos/métodos , Hormônio do Crescimento Humano/genética , Fator de Crescimento Insulin-Like I/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Lactente , Fator de Crescimento Insulin-Like I/metabolismo , Masculino
15.
Sci Rep ; 10(1): 13763, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792680

RESUMO

Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the effect of loss of SNX14 in mice, which resulted in embryonic lethality around mid-gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. In contrast to other vertebrates, zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation were both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. Mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.


Assuntos
Viabilidade Fetal/genética , Metabolismo dos Lipídeos/genética , Placenta/anormalidades , Nexinas de Classificação/genética , Ataxias Espinocerebelares/genética , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Fenótipo , Fosfolipídeos/sangue , Gravidez , Trofoblastos/citologia , Peixe-Zebra
16.
F1000Res ; 8: 90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497289

RESUMO

Background: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a key negative regulator of cell growth encoded by a paternally imprinted/maternally expressed gene in humans. Loss-of-function variants in CDKN1C are associated with an overgrowth condition (Beckwith-Wiedemann Syndrome) whereas "gain-of-function" variants in CDKN1C that increase protein stability cause growth restriction as part of IMAGe syndrome ( Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia and Genital anomalies). As three families have been reported with CDKN1C mutations who have fetal growth restriction (FGR)/Silver-Russell syndrome (SRS) without adrenal insufficiency, we investigated whether pathogenic variants in CDKN1C could be associated with isolated growth restriction or recurrent loss of pregnancy. Methods: Analysis of published literature was undertaken to review the localisation of variants in CDKN1C associated with IMAGe syndrome or fetal growth restriction. CDKN1C expression in different tissues was analysed in available RNA-Seq data (Human Protein Atlas). Targeted sequencing was used to investigate the critical region of CDKN1C for potential pathogenic variants in SRS (n=66), FGR (n=37), DNA from spontaneous loss of pregnancy (n= 22) and women with recurrent miscarriages (n=78) (total n=203). Results: All published single nucleotide variants associated with IMAGe syndrome are located in a highly-conserved "hot-spot" within the PCNA-binding domain of CDKN1C between codons 272-279. Variants associated with familial growth restriction but normal adrenal function currently affect codons 279 and 281. CDKN1C is highly expressed in the placenta compared to adult tissues, which may contribute to the FGR phenotype and supports a role in pregnancy maintenance. In the patient cohorts studied no pathogenic variants were identified in the PCNA-binding domain of CDKN1C. Conclusion: CDKN1C is a key negative regulator of growth. Variants in a very localised "hot-spot" cause growth restriction, with or without adrenal insufficiency. However, pathogenic variants in this region are not a common cause of isolated fetal growth restriction phenotypes or loss-of-pregnancy/recurrent miscarriages.


Assuntos
Aborto Habitual/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Retardo do Crescimento Fetal/genética , Insuficiência Adrenal/genética , Adulto , Feminino , Humanos , Osteocondrodisplasias/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Anormalidades Urogenitais/genética
17.
Chem Commun (Camb) ; (40): 4909-11, 2008 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-18931735

RESUMO

Densely packed co-adsorbed ultrathin mono molecular layers of short tri(ethylene glycol)-alkanethiolate (for repelling proteins) and maltoside terminated alkanethiolate (for capturing lectin) provided an extremely high signal to noise ratio surface: the repelling molecules, which had two different functions (highly flexible-hydrophilic arm and rigid packing tail group), worked as "nano barriers" in the recognition monolayer.


Assuntos
Alcanos/química , Concanavalina A/análise , Concanavalina A/química , Polietilenoglicóis/química , Compostos de Sulfidrila/química , Adsorção , Animais , Bovinos , Peptídeos/química , Sensibilidade e Especificidade
19.
J Clin Endocrinol Metab ; 103(3): 917-925, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29342293

RESUMO

Context: Small for gestational age (SGA) can be the result of fetal growth restriction, which is associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the current study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more copy number variations (CNVs) and disturbed methylation and sequence variants may be present in genes associated with fetal growth. Design: A prospective cohort study of subjects with a low birth weight for gestational age. Setting: The study was conducted at an academic pediatric research institute. Patients: A total of 21 SGA newborns with a mean birth weight below the first centile and a control cohort of 24 appropriate-for-gestational-age newborns were studied. Interventions: Array comparative genomic hybridization, genome-wide methylation studies, and exome sequencing were performed. Main Outcome Measures: The numbers of CNVs, methylation disturbances, and sequence variants. Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern, and one sequence variant explaining SGA. Additional methylation disturbances and sequence variants were present in 20 patients. In 19 patients, multiple abnormalities were found. Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We concluded that CNVs, methylation disturbances, and sequence variants all contribute to prenatal growth failure. These genetic workups can be an effective diagnostic approach in SGA newborns.


Assuntos
Peso ao Nascer/genética , Retardo do Crescimento Fetal/genética , Recém-Nascido Pequeno para a Idade Gestacional , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Metilação de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos , Sequenciamento do Exoma/métodos
20.
Anim Sci J ; 88(3): 468-475, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27444406

RESUMO

To examine the effects of inclusion levels of pelleted silvergrass (PS) in the diet on digestibility, ruminal fermentation and nutrient status of breeding Japanese Black cows, four cows were allotted to a 4 × 4 Latin square design experiment. Treatments were control fed a diet consisting of 89.4% Sudangrass hay and 10.6% soybean meal on a dry matter (DM) basis, and PS18, PS27 and PS45 fed the diet replaced with 18%, 27% and 45% of control with PS, respectively. The total digestible nutrients (TDN) content of PS was 45.6% on a DM basis. The TDN intakes were significantly decreased by increasing PS level in the diet (P < 0.05), but were higher than the TDN requirement of maintenance cows in all treatments. The total chewing time was decreased significantly by increasing PS level in the diets (P < 0.05). However, the pH and concentration of volatile fatty acid in the ruminal fluid and serum metabolite concentrations were not significantly different among the treatments. The results suggested that including PS up to 45% in the diet did not have adverse effects on the ruminal fermentation and nutrient status in breeding Japanese Black cows at the maintenance stage.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Bovinos/fisiologia , Dieta/veterinária , Fenômenos Fisiológicos do Sistema Digestório , Fermentação , Mastigação/fisiologia , Poaceae , Rúmen/fisiologia , Ração Animal , Animais , Bovinos/sangue , Digestão , Ácidos Graxos Voláteis/metabolismo , Feminino , Concentração de Íons de Hidrogênio , Rúmen/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA