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1.
Mov Disord ; 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39235665

RESUMO

BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene. OBJECTIVE: The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age-matched healthy subjects (n = 87). METHODS: LTL was measured by real-time polymerase chain reaction quantitative analysis (qPCR). RESULTS: The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)-like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair. CONCLUSIONS: Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

2.
Int J Mol Sci ; 25(5)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38474154

RESUMO

A comprehensive gene expression investigation requires high-quality RNA extraction, in sufficient amounts for real-time quantitative polymerase chain reaction and next-generation sequencing. In this work, we compared different RNA extraction methods and evaluated different reference genes for gene expression studies in the fetal human inner ear. We compared the RNA extracted from formalin-fixed paraffin-embedded tissue with fresh tissue stored at -80 °C in RNAlater solution and validated the expression stability of 12 reference genes (from gestational week 11 to 19). The RNA from fresh tissue in RNAlater resulted in higher amounts and a better quality of RNA than that from the paraffin-embedded tissue. The reference gene evaluation exhibited four stably expressed reference genes (B2M, HPRT1, GAPDH and GUSB). The selected reference genes were then used to examine the effect on the expression outcome of target genes (OTOF and TECTA), which are known to be regulated during inner ear development. The selected reference genes displayed no differences in the expression profile of OTOF and TECTA, which was confirmed by immunostaining. The results underline the importance of the choice of the RNA extraction method and reference genes used in gene expression studies.


Assuntos
Perfilação da Expressão Gênica , RNA , Humanos , Perfilação da Expressão Gênica/métodos , Gliceraldeído-3-Fosfato Desidrogenases/genética , Expressão Gênica , Reação em Cadeia da Polimerase em Tempo Real
3.
Mov Disord ; 38(6): 959-969, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36433650

RESUMO

BACKGROUND: Optic neuropathy is a near ubiquitous feature of Friedreich's ataxia (FRDA). Previous studies have examined varying aspects of the anterior and posterior visual pathways but none so far have comprehensively evaluated the heterogeneity of degeneration across different areas of the retina, changes to the macula layers and combined these with volumetric MRI studies of the visual cortex and frataxin level. METHODS: We investigated 62 genetically confirmed FRDA patients using an integrated approach as part of an observational cohort study. We included measurement of frataxin protein levels, clinical evaluation of visual and neurological function, optical coherence tomography to determine retinal nerve fibre layer thickness and macular layer volume and volumetric brain MRI. RESULTS: We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. CONCLUSION: Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Ataxia de Friedreich , Doenças do Nervo Óptico , Humanos , Vias Visuais/diagnóstico por imagem , Ataxia de Friedreich/genética , Acuidade Visual , Retina/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos
4.
Mov Disord ; 37(2): 405-410, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34713931

RESUMO

BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Machado-Joseph , Ataxias Espinocerebelares , Humanos , Estilo de Vida , Estudos Prospectivos , Índice de Gravidade de Doença , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/epidemiologia
5.
Eur J Neurol ; 29(8): 2439-2452, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35478426

RESUMO

BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures. METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels. RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001). CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.


Assuntos
Doença de Machado-Joseph , Proteínas de Neurofilamentos , Proteínas tau , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cerebelo/química , Heterozigoto , Humanos , Doença de Machado-Joseph/sangue , Doença de Machado-Joseph/líquido cefalorraquidiano , Doença de Machado-Joseph/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
6.
bioRxiv ; 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39386730

RESUMO

During development, precursor cells are continuously and intimately interacting with their extracellular environment, which guides their ability to generate functional tissues and organs. Much is known about the development of the neocortex in mammals. This information has largely been derived from histological analyses, heterochronic cell transplants, and genetic manipulations in mice, and to a lesser extent from transcriptomic and histological analyses in humans. However, these approaches have not led to a characterization of the extracellular composition of the developing neocortex in any species. Here, using a combination of single-cell transcriptomic analyses from published datasets, and our proteomics and immunohistofluorescence analyses, we provide a more comprehensive and unbiased picture of the early developing fetal neocortex in humans and non-human primates. Our findings provide a starting point for further hypothesis-driven studies on structural and signaling components in the developing cortex that had previously not been identified.

7.
J Neurol ; 270(2): 944-952, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36324033

RESUMO

BACKGROUND: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. OBJECTIVE: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. METHODS: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. RESULTS: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. CONCLUSION: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle.


Assuntos
Síndrome das Pernas Inquietas , Humanos , Síndrome das Pernas Inquietas/epidemiologia , Estudos Prospectivos , Estudos Transversais , Atividades Cotidianas , Gravidade do Paciente , Estilo de Vida
8.
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
9.
Antioxidants (Basel) ; 11(8)2022 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-35892638

RESUMO

SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.

10.
Ann Clin Transl Neurol ; 8(2): 321-331, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33338328

RESUMO

BACKGROUND: Little information is available in spinocerebellar ataxias (SCAs) regarding pelvic organ symptoms. The aim of this study was to characterize the lower urinary tract (LUT) and bowel dysfunction in autosomal dominant spinocerebellar ataxias. METHODS: Patients with confirmed SCAs attending a tertiary care service were approached about LUT and bowel complaints, and completed validated questionnaires: urinary symptom profile (USP), Qualiveen-Short form, International Prostate Symptom Score, and Neurogenic Bowel Dysfunction Score. SCA3 and SCA7 patients with urological complaints additionally underwent urodynamic studies (UDS). Patients' characterization included demographic, clinical (Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Signs (INAS)), and genetic variables. Descriptive and comparative analyses were performed. RESULTS: Fifty-one patients participated: SCA1 (n = 4), SCA2 (n = 11), SCA3 (n = 13), SCA6 (n = 17), and SCA7 (n = 6). The prevalence of self-reported LUT symptoms was 60.8% (n = 31), whereas LUT symptoms was reported in 86.3%(n = 44) using the USP. Both storage and voiding symptoms were reported, urinary frequency and urgency being the most frequent (n = 34, 68%). Although LUT symptoms were most often classed as mild (n = 27, 61.4%), they impacted QoL in 38 patients (77.6%). Of these, 21 (55.3%) were not on pharmacological treatment for urinary dysfunction. Most common abnormalities in UDS (n = 14) were detrusor overactivity (storage phase) and detrusor underactivity (voiding phase). Bowel symptoms were less common (31.4%, n = 16) and of mild severity. CONCLUSION: LUT symptoms are prevalent in SCA patients and impact QoL, whereas bowel symptoms tend to be mild. These symptoms are overlooked by patients and physicians due to the complexity of neurological involvement in SCA, and therefore a multidisciplinary management approach should be adopted.


Assuntos
Intestinos/fisiopatologia , Próstata/fisiopatologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Sistema Urinário/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Índice de Gravidade de Doença , Urodinâmica
11.
Kidney Int ; 78(7): 660-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20631677

RESUMO

Erythropoietin is produced by the kidney and stimulates erythropoiesis; however, in chronic renal disease its levels are reduced and patients develop anemia that is treatable with iron and recombinant hormone. The mechanism by which erythropoietin improves iron homeostasis is still unclear, but it may involve suppression of the iron regulatory peptide hepcidin and/or a direct effect on intestinal iron absorption. To investigate these possibilities, we used the well-established 5/6th nephrectomy rat model of chronic renal failure with or without human recombinant erythropoietin treatment. Monolayers of human intestinal Caco-2 cells were also treated with erythropoietin to measure any direct effects of this hormone on intestinal iron transport. Nephrectomy increased hepatic hepcidin expression and decreased intestinal iron absorption; these effects were restored to levels found in sham-operated rats on erythropoietin treatment of the rats with renal failure. In Caco-2 cells, the addition of erythropoietin significantly increased the expression of apical divalent metal transporter 1 (DMT1) and basolateral ferroportin and, consequently, iron transport across the monolayer. Taken together, our results show that erythropoietin not only exerts a powerful inhibitory action on the expression of hepcidin, thus permitting the release of iron from reticuloendothelial macrophages and intestinal enterocytes, but also acts directly on enterocytes to increase iron absorption.


Assuntos
Eritropoetina/farmacologia , Absorção Intestinal/efeitos dos fármacos , Ferro/metabolismo , Falência Renal Crônica/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Células CACO-2 , Proteínas de Transporte de Cátions/genética , Modelos Animais de Doenças , Duodeno/metabolismo , Hepcidinas , Humanos , Masculino , Nefrectomia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptores da Eritropoetina/análise , Transdução de Sinais
12.
Biometals ; 22(2): 211-23, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18690415

RESUMO

The effects of changes in macrophage iron status, induced by single or multiple iron injections, iron depletion or pregnancy, on both immune function and mRNA expression of genes involved in iron influx and egress have been evaluated. Macrophages isolated from iron deficient rats, or pregnant rats at day 21 of gestation, either supplemented with a single dose of iron dextran, 10 mg, at the commencement of pregnancy, or not, showed significant increases of macrophage ferroportin mRNA expression, which was paralleled by significant decreases in hepatic Hamp mRNA expression. IRP activity in macrophages was not significantly altered by iron status or the inducement of pregnancy +/- a single iron supplement. Macrophage immune function was significantly altered by iron supplementation and pregnancy. Iron supplementation, alone or combined with pregnancy, increased the activities of both NADPH oxidase and nuclear factor kappa B (NFkappaB). In contrast, the imposition of pregnancy reduced the ability of these parameters to respond to an inflammatory stimuli. Increasing iron status, if only marginally, will reduce the ability of macrophages to mount a sustained response to inflammation as well as altering iron homeostatic mechanisms.


Assuntos
Ferro/toxicidade , Macrófagos/citologia , Alvéolos Pulmonares/metabolismo , Animais , Feminino , Homeostase , Sistema Imunitário , Inflamação , Macrófagos/metabolismo , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase/metabolismo , Gravidez , Prenhez , Ratos , Ratos Wistar
13.
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
15.
Birth Defects Res ; 110(5): 443-455, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29316344

RESUMO

BACKGROUND: MC1R, a G-protein coupled receptor with high affinity for alpha-melanocyte stimulating hormone (αMSH), modulates pigment production in melanocytes from many species and is associated with human melanoma risk. MC1R mutations affecting human skin and hair color also have pleiotropic effects on the immune response and analgesia. Variants affecting human pigmentation in utero alter the congenital phenotype of both oculocutaneous albinism and congenital melanocytic naevi, and have a possible effect on birthweight. METHODS AND RESULTS: By in situ hybridization, RT-PCR and immunohistochemistry, we show that MC1R is widely expressed during human, chick and mouse embryonic and fetal stages in many somatic tissues, particularly in the musculoskeletal and nervous systems, and conserved across evolution in these three amniotes. Its dynamic pattern differs from that of TUBB3, a gene overlapping the same locus in humans and encoding class III ß-tubulin. The αMSH peptide and the transcript for its precursor, pro-opiomelanocortin (POMC), are similarly present in numerous extra-cutaneous tissues. MC1R genotyping of variants p.(V60M) and p.(R151C) was undertaken for 867 healthy children from the Avon Longitudinal Study of Parent and Children (ALSPAC) cohort, and birthweight modeled using multiple logistic regression analysis. A significant positive association initially found between R151C and birth weight, independent of known birth weight modifiers, was not reproduced when combined with data from an independent genome-wide association study of 6,459 additional members of the same cohort. CONCLUSIONS: These data clearly show a new and hitherto unsuspected role for MC1R in noncutaneous solid tissues before birth.


Assuntos
Proteínas Aviárias/biossíntese , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Receptor Tipo 1 de Melanocortina/biossíntese , Animais , Embrião de Galinha , Embrião de Mamíferos/citologia , Humanos , Camundongos
16.
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
17.
Reprod Sci ; 24(7): 1070-1078, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27879450

RESUMO

Methionine demethylation during metabolism generates homocysteine (Hcy) and its remethylation requires folate and cobalamin. Elevated Hcy concentrations are associated with vascular-related complications of pregnancy, including increased vascular stiffness, predictive of clinical vascular disease. Maternal and fetal total Hcy (tHcy) concentrations are positively related, yet the influence of Hcy on fetoplacental vascular function in normal pregnancy has not been examined. We hypothesized that Hcy alters fetoplacental vascular characteristics with influences on fetal growth outcomes. We investigated (1) placental chorionic plate artery distensibility and neonatal blood pressure in relation to umbilical plasma tHcy; (2) relationships between cord venous (CV) and cord arterial (CA) plasma tHcy, folate, and cobalamin concentrations; and (3) tHcy associations with birth weight and anthropometric measurements of body size as indices of fetal growth in normal pregnancies with appropriate weight-for-gestational age newborns. Maternal plasma tHcy, folate, and cobalamin concentrations were consistent with published data. Placental chorionic plate artery distensibility index (ß; measure of vessel stiffness) was inversely related to CA tHcy, yet neonatal blood pressure was not significantly affected. CV and CA tHcy concentrations were positively related and CV tHcy negatively related to CV cobalamin but not folate. CV tHcy concentration positively related to birth weight, corrected birth weight percentile, length, head circumference, and mid-arm circumference of newborns. CV cobalamin was inversely related to fetal growth indices but not to folate concentration. Our study demonstrates a potential relationship between fetal tHcy and placental artery distensibility, placing clinical relevance to cobalamin in influencing Hcy concentration and maintaining low vascular resistance to facilitate nutrient exchange favorable to fetal growth.


Assuntos
Artérias/fisiologia , Peso ao Nascer/fisiologia , Tamanho Corporal/fisiologia , Sangue Fetal/metabolismo , Homocisteína/sangue , Placenta/irrigação sanguínea , Pressão Sanguínea/fisiologia , Feminino , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez
18.
Placenta ; 46: 31-37, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27697219

RESUMO

About 20% of pregnancies are affected by some form of complication. Research has shown that anomalies in implantation, development, and growth of the fetus; ineffective nutrient exchange between mother and fetus due to placental dysfunction; and maternal problems such as hypertension or infection during pregnancy can all lead to adverse pregnancy outcomes. However, the molecular aetiology of such events remains poorly understood. Fetal growth restriction (FGR), recurrent miscarriage (RM), preterm birth (PTB), and pre-eclampsia (PE) are the most common pregnancy complications encountered in the UK and these outcomes can result in an array of morbidities in both mother and baby, and in the most severe cases in mortality. We need to know more about normal pregnancy and where the important triggers are for failure. This prompted us to collect a large set of biological samples with matching clinical data from over 2500 normal and abnormal pregnancies, for use in research into these conditions. This paper outlines the nature of these sample sets and their availability to academia and industry, with the intention that their widespread use in research will make significant contributions to the improvement of maternal and fetal health worldwide (http://www.ucl.ac.uk/tapb/sample-and-data-collections-at-ucl/biobanks-ucl/baby-biobank).


Assuntos
Bancos de Espécimes Biológicos , Bases de Dados como Assunto , Complicações na Gravidez , Feminino , Humanos , Gravidez , Manejo de Espécimes
19.
Basic Clin Pharmacol Toxicol ; 94(4): 161-8, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15078340

RESUMO

The relationship between haem biosynthesis and intestinal iron absorption in mice was investigated by ascertaining the effect of the haem synthesis inhibitor, griseofulvin, on duodenal iron absorption using both in vivo and in vitro measurements. Urinary 5-aminolaevulinic acid levels were increased within 24 hr of feeding mice with griseofulvin diet (2.5% w/w), with more marked increases seen after 3-7 days. Urinary porphobilinogen levels also showed a similar trend. In vivo intestinal iron absorption was significantly reduced (P<0.05) in experimental mice, mainly due to reduction in the transfer of 59Fe from the enterocytes to the portal circulation. In vitro studies using isolated duodenal fragments also exhibited marked decreases in both iron uptake and Fe (III) reduction. Changes in mucosal Divalent Metal Transporter 1 (DMT-1), Dcytb and Ireg1 (iron regulated protein 1) mRNA levels paralleled the changes in iron absorption. The reduction in iron absorption after griseofulvin treatment was normalised when mice were simultaneously injected with haem-arginate. These data support the hypothesis that intermediates in haem biosynthesis, particularly 5-aminolaevulinic acid, regulate intestinal iron absorption.


Assuntos
Griseofulvina/farmacologia , Heme/antagonistas & inibidores , Absorção Intestinal/efeitos dos fármacos , Ferro da Dieta/farmacocinética , Administração Oral , Ácido Aminolevulínico/urina , Animais , Transporte Biológico/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Proteínas de Transporte de Cátions/biossíntese , Proteínas de Transporte de Cátions/genética , Interações Medicamentosas , Duodeno/metabolismo , Expressão Gênica/efeitos dos fármacos , Heme/biossíntese , Técnicas In Vitro , Proteínas de Ligação ao Ferro/biossíntese , Proteínas de Ligação ao Ferro/genética , Fígado/metabolismo , Fígado/fisiologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Porfobilinogênio/urina
20.
J Physiol ; 552(Pt 2): 603-10, 2003 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-14561840

RESUMO

Iron (Fe) deficiency anaemia during pregnancy results in an increased risk of perinatal mortality and morbidity and is a significant factor for increased risk of disease in later life. Consequently we have developed a rat model to study the relationship between maternal Fe deficiency and postnatal growth and blood pressure in the offspring. Weanlings were fed a control or Fe-deficient diet prior to and throughout pregnancy. At term, all pups were cross-fostered to control fed dams and weaned onto control diet. At birth, pups from deficient dams had a greater mortality rate, were smaller and had reduced haematocrit and liver Fe levels. They also had larger hearts, smaller kidneys and spleens and unchanged livers (relative organ weight). The pups grew normally. At 6 weeks, male pups from deficient dams had a higher and females a lower blood pressure than their normal counterparts. At 10 and 16 weeks, blood pressure in the males from deficient dams was still raised and in the females was now greater than controls. The haematocrit was lower in males throughout the 16 weeks and in females until 10 weeks of age. There was no significant difference in the offsprings' liver Fe stores at 6, 10 or 16 weeks. Duodenal Fe uptake in both the Fe-deficient mother and newborn offspring was significantly increased. By cross-fostering, we have eliminated confounding factors, such as maternal anaemia during lactation and show, unequivocally, that prenatal nutrition is critical for the development of normal postnatal function.


Assuntos
Animais Recém-Nascidos/fisiologia , Pressão Sanguínea/fisiologia , Deficiências de Ferro , Prenhez/fisiologia , Animais , Peso Corporal/fisiologia , Dieta , Duodeno/metabolismo , Feminino , Teste de Tolerância a Glucose , Hematócrito , Insulina/sangue , Radioisótopos de Ferro , Estado Nutricional , Gravidez , Ratos , Espectrofotometria Atômica
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