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1.
Hum Mol Genet ; 31(9): 1389-1406, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34761259

RESUMO

Autism spectrum disorder (ASD) and intellectual disability (ID) often exist together in patients. The RAB39B gene has been reported to be mutated in ID patients with additional clinical features ranging from ASD, macrocephaly, seizures and/or early-onset parkinsonism. Here, we describe a novel RAB39B nonstop mutation [Xq28; c.640 T > C; p.(*214Glnext*21)] in a family with ASD, severe ID and poor motor coordination, and we assessed the pathogenicity of the mutation. A heterologous cell system and a Rab39b knockdown (KD) murine model, which mimic the nonstop mutation, were used to validate the deleterious effect of the RAB39B mutation. The mutation led to RAB39B protein instability, resulting in its increased degradation and consequent downregulation. Using a Rab39b KD mouse model, we demonstrated that the downregulation of RAB39B led to increased GluA2 lacking Ca2+-permeable AMPAR composition at the hippocampal neuronal surface and increased dendritic spine density that remained in an immature filopodia-like state. These phenotypes affected behavioural performance in a disease-specific manner. Rab39b KD mice revealed impaired social behaviour but intact social recognition. They also showed normal anxiety-like, exploratory and motivational behaviours but impaired working and associative memories. In conclusion, we found a novel RAB39B nonstop variant that segregated in a family with a clinical phenotype including ID, ASD and poor motor coordination. The pathogenicity of mutations causing the downregulation of RAB39B proteins, impacting AMPAR trafficking and dendritic spine morphogenesis, reinforced the idea that AMPAR modulation and dendritic spine assets could be considered hallmarks of neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Animais , Transtorno do Espectro Autista/genética , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Deficiência Intelectual/genética , Camundongos , Mutação , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
2.
Hematol Oncol ; 41(5): 942-946, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37534633

RESUMO

TNFRSF13B mutations are widely associated with common variable immunodeficiency. TNFRSF13B was recently counted among relevant genes associated with childhood-onset of hematological malignancies; nonetheless, its role in acute myeloid leukemia (AML) remains unexplored. We report the study of a family with two cases of AML, sharing a germline TNFRSF13B mutation favoring the formation of a more stable complex with its ligand TNFSF13: a positive regulator of AML-initiating cells. Our data turn the spotlight onto the TNFRSF13B role in AML onset, inserting a new fragment into the complex scenario of a hereditary predisposition to myeloid neoplasms.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Criança , Mutação , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , Leucemia Mieloide Aguda/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética
3.
J Med Genet ; 59(2): 189-195, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33361104

RESUMO

BACKGROUND: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1. It was mainly described in children. METHODS: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood. RESULTS: Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1. All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited. CONCLUSIONS: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.


Assuntos
Anormalidades Múltiplas/patologia , Deficiência Intelectual/patologia , Proteínas Nucleares/genética , Anormalidades Múltiplas/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Adulto Jovem
4.
Int J Mol Sci ; 24(15)2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37569667

RESUMO

Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPDII) represents the most common form of primordial dwarfism. MOPD clinical features include severe prenatal and postnatal growth retardation, postnatal severe microcephaly, hypotonia, and an increased risk for cerebrovascular disease and insulin resistance. Autosomal recessive biallelic loss-of-function genomic variants in the centrosomal pericentrin (PCNT) gene on chromosome 21q22 cause MOPDII. Over the past decade, exome sequencing (ES) and massive RNA sequencing have been effectively employed for both the discovery of novel disease genes and to expand the genotypes of well-known diseases. In this paper we report the results both the RNA sequencing and ES of three patients affected by MOPDII with the aim of exploring whether differentially expressed genes and previously uncharacterized gene variants, in addition to PCNT pathogenic variants, could be associated with the complex phenotype of this disease. We discovered a downregulation of key factors involved in growth, such as IGF1R, IGF2R, and RAF1, in all three investigated patients. Moreover, ES identified a shortlist of genes associated with deleterious, rare variants in MOPDII patients. Our results suggest that Next Generation Sequencing (NGS) technologies can be successfully applied for the molecular characterization of the complex genotypic background of MOPDII.


Assuntos
Nanismo , Microcefalia , Osteocondrodisplasias , Humanos , Feminino , Gravidez , Microcefalia/genética , Exoma/genética , Transcriptoma , Retardo do Crescimento Fetal/genética , Nanismo/genética , Osteocondrodisplasias/genética , Genótipo , Mutação
5.
Eur J Neurol ; 29(7): 2156-2161, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35253317

RESUMO

BACKGROUND AND PURPOSE: Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. METHODS: After unremarkable whole-exome sequencing (WES) analysis, we performed repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. RESULTS: In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1-/- cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). CONCLUSIONS: We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.


Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Neuropatias Hereditárias Sensoriais e Autônomas , Doenças do Sistema Nervoso Periférico , Doenças Vestibulares , Ataxia , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Tosse/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Humanos , Doenças do Sistema Nervoso Periférico/complicações
6.
Prenat Diagn ; 42(13): 1575-1586, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36403097

RESUMO

OBJECTIVES: To establish the positive predictive values (PPV) of cfDNA testing based on data from a nationwide survey of independent clinical cytogenetics laboratories. METHODS: Prenatal diagnostic test results obtained by Italian laboratories between 2013 and March 2020 were compiled for women with positive non-invasive prenatal tests (NIPT), without an NIPT result, and cases where there was sex discordancy between the NIPT and ultrasound. PPV and other summary data were reviewed. RESULTS: Diagnostic test results were collected for 1327 women with a positive NIPT. The highest PPVs were for Trisomy (T) 21 (624/671, 93%) and XYY (26/27, 96.3%), while rare autosomal trisomies (9/47, 19.1%) and recurrent microdeletions (8/55, 14.5%) had the lowest PPVs. PPVs for T21, T18, and T13 were significantly higher when diagnostic confirmation was carried out on chorionic villi (97.5%) compared to amniotic fluid (89.5%) (p < 0.001). In 19/139 (13.9%), of no result cases, a cytogenetic abnormality was detected. Follow-up genetic testing provided explanations for 3/6 cases with a fetal sex discordancy between NIPT and ultrasound. CONCLUSIONS: NIPT PPVs differ across the conditions screened and the tissues studied in diagnostic testing. This variability, issues associated with fetal sex discordancy, and no results, illustrate the importance of pre- and post-test counselling.


Assuntos
Ácidos Nucleicos Livres , Feminino , Humanos , Gravidez , Análise Citogenética , Valor Preditivo dos Testes , Diagnóstico Pré-Natal/métodos , Trissomia/diagnóstico , Trissomia/genética , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Itália
7.
Clin Genet ; 99(3): 425-429, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33236357

RESUMO

mTOR dysregulation has been described in pathological conditions, such as cardiovascular and overgrowth disorders. Here we report on the first case of a patient with a complex congenital heart disease and an interstitial duplication in the short arm of chromosome 1, encompassing part of the mTOR gene. Our results suggest that an intragenic mTOR microduplication might play a role in the pathogenesis of non-syndromic congenital heart defects (CHDs) due to an upregulation of mTOR/Rictor and consequently an increased phosphorylation of PI3K/AKT and MEK/ERK signaling pathways in patient-derived amniocytes. This is the first report which shows a causative role of intragenic mTOR microduplication in the etiology of an isolated complex CHD.


Assuntos
Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Cromossomos Humanos Par 1 , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
8.
Am J Med Genet A ; 185(6): 1897-1902, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33750022

RESUMO

RASopathies are a group of syndromes with partially overlapping clinical features caused by germline mutations of the RAS/MAPK signaling pathway genes. The most common disorder is Noonan syndrome (NS; MIM 163950). We report the first prenatal case of NS with SOS2 (NM_006939.4) mutation in a euploid fetus with a severe increase in nuchal translucency (NT > 12 mm). Trio-based custom next-generation sequencing detected a de novo heterozygous missense mutation in the SOS2 gene: c.800 T > A (p.Met267Lys). Owing to the marked variable expressivity of NS and the scarcity of SOS2 mutation-related NS cases reported in the literature, it is difficult to provide appropriate genetic counseling. Several issues such as the best management technique and optimal NT cutoff have been discussed. In addition, in general, the fine balance between the advantages of an early prenatal diagnosis and the challenge of determining if the detected gene variant is pathogenic and, primarily, the stress of the counselees when providing a genetic counseling with limited information on the prenatal phenotype have been discussed. A prenatal path comprising examinations and multidisciplinary counseling is essential to support couples in a shared decision-making process.


Assuntos
Diagnóstico Precoce , Predisposição Genética para Doença , Síndrome de Noonan/diagnóstico , Proteínas Son Of Sevenless/genética , Feminino , Feto/diagnóstico por imagem , Feto/patologia , Aconselhamento Genético , Humanos , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/diagnóstico por imagem , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Linhagem , Diagnóstico Pré-Natal
9.
Medicina (Kaunas) ; 57(12)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34946295

RESUMO

Background: Cleidocranial dysplasia (CCD) is a rare, autosomal dominant skeletal dysplasia with a prevalence of one per million births. The main causes of CCD are mutations in the core-binding factor alpha-1 (CBFA1) or runt-related transcription factor-2 (RUNX2), located at the 6p21 chromosomal region. RUNX2 plays important roles in osteoblast differentiation, chondrocyte proliferation and differentiation, and tooth formation. The disease is characterized by clavicular aplasia or hypoplasia, Wormian bones, delayed closure of cranial suture, brachycephalic head, maxillary deficiency, retention of primary teeth, inclusion of permanent teeth, and multiple supernumerary teeth. Materials and Methods: A 22-year-old girl suffering from cleidocranial dysplasia with short stature, narrow shoulders, craniofacial manifestations (short face, broad forehead, etc.) and dental anomalies (different lower dental elements under eruption, supernumerary and impacted multiple teeth, etc.) was examined at our service (Complex Operative Unit of Odontostomatology of Policlinico of Bari). RX Orthopantomography (OPG) and cone beam computed tomography (CBCT) were requested to better assess the position of the supernumerary teeth and their relationships with others and to evaluate the bone tissue. Results: Under eruption was probably caused by dental interferences with supernumerary teeth; hence, extractions of supernumerary upper canines and lower premolars were performed under general anaesthesia. Surgery outcome was excellent with good tissue healing and improvements in the therapeutic possibilities with future orthodontics. Conclusions: The objective of this article is to give an update about radiological, clinical, and molecular features of CCD and to alert the health team about the importance of establishing an early diagnosis and an appropriate treatment in these patients to prevent impacted teeth complications and to offer them a better quality of life.


Assuntos
Displasia Cleidocraniana , Dente Impactado , Dente Supranumerário , Adulto , Displasia Cleidocraniana/genética , Feminino , Humanos , Qualidade de Vida , Radiografia Panorâmica , Dente Impactado/diagnóstico por imagem , Dente Impactado/genética , Dente Impactado/cirurgia , Dente Supranumerário/diagnóstico por imagem , Dente Supranumerário/genética , Dente Supranumerário/cirurgia , Adulto Jovem
10.
Prenat Diagn ; 40(11): 1474-1481, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33034897

RESUMO

OBJECTIVE: To examine the incidence and type of chromosomal abnormalities in fetuses with first trimester ultrasound anomalies and a low-risk cfDNA test for common trisomies. METHODS: In 486 singleton pregnancies undergoing invasive testing after combined screening, a detailed first trimester ultrasound assessment was carried out and a maternal blood sample was sent for cfDNA analysis. Ultrasound and cfDNA data were analyzed in relation to fetal karyotype. RESULTS: Invasive testing demonstrated a chromosomal abnormality in 157 (32.3%) of 486 fetuses. In 348 cases with a low-risk cfDNA test for common trisomies, NT ≥ 3.5 mm and/or a major structural defect were observed in 92 (26.4%) fetuses. A chromosomal abnormality was found in 17 (18.5%; 95%CI 10.55-26.41) of these pregnancies, including 1 (1.1%) case of trisomy 21 and 16 (17.4%) fetuses with abnormalities different from common trisomies. The respective incidence in the 256 cases with a low-risk cfDNA test result and no ultrasound anomalies was 2.3% (95% CI 0.49-4.20; n = 6). CONCLUSIONS: In fetuses with first trimester ultrasound anomalies and a low-risk cfDNA result for trisomy 21, 18 and 13, diagnostic testing should be offered with the main objective to detect chromosomal abnormalities beyond common trisomies.


Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Anormalidades Congênitas/genética , Medição da Translucência Nucal , Adulto , Ácidos Nucleicos Livres/análise , Anormalidades Congênitas/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Trissomia/diagnóstico , Adulto Jovem
11.
Clin Genet ; 95(1): 165-171, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288735

RESUMO

Biallelic exostosin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently, it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here, we report the third family affected by AREXT2 syndrome, harboring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families. AREXT2 syndrome can be considered as a multiorgan Congenital Disorder of Glycosylation caused by a significant, but non-lethal, decrease in EXT2 expression, thereby affecting the synthesis of the heparan sulfate proteoglycans, which is relevant in many physiological processes. Our finding expands the clinical and molecular spectrum of the AREXT2 syndrome and suggests a possible genotype/phenotype correlation in the development of the exostoses.


Assuntos
Exostose Múltipla Hereditária/genética , Deficiência Intelectual/genética , N-Acetilglucosaminiltransferases/genética , Convulsões/genética , Adulto , Ecocardiografia , Exostose Múltipla Hereditária/diagnóstico por imagem , Exostose Múltipla Hereditária/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Adulto Jovem
12.
Fetal Diagn Ther ; 46(3): 149-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30352439

RESUMO

OBJECTIVE: To estimate the procedure-related risk of miscarriage in pregnancies undergoing amniocentesis (AC) following inconclusive results for a chorionic villus sampling (CVS). METHODS: This was a multicentric retrospective cohort study of patients in which both CVS at 11-13 weeks' gestation and AC at 16-22 weeks were performed between January 1st, 2008, and July 31st, 2017. The primary outcome measure was pregnancy loss prior to 24 weeks gestation; the secondary one was intrauterine demise after 24 weeks. RESULTS: A total of 287 patients underwent transabdominal CVS and AC. Nine patients were lost at follow-up; therefore, the analysis was conducted on a population of 278 patients (275 singletons and 3 dichorionic twin pregnancies). AC was performed because of placental mosaicism (93.6%), failure of direct/semidirect preparation of trophoblastic cells (3.2%), or targeted genetic testing after the diagnosis of an anomaly in the second trimester (3.2%). In continuing pregnancies, there were no fetal losses prior to 24 weeks' gestation. Two intrauterine demises (including 1 fetus with multiple anomalies and growth restriction) in the third trimester were recorded. CONCLUSION: Patients undergoing midtrimester AC because of an inconclusive result of CVS can be reasonably reassured that in general the risk of miscarriage and fetal loss following the procedure is very small.


Assuntos
Aborto Espontâneo/etiologia , Amniocentese/efeitos adversos , Morte Fetal/etiologia , Adulto , Amostra da Vilosidade Coriônica , Feminino , Humanos , Gravidez , Segundo Trimestre da Gravidez , Cuidado Pré-Natal , Estudos Retrospectivos , Fatores de Risco
13.
Int J Mol Sci ; 18(8)2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28829357

RESUMO

Malignant mesothelioma is a rare and aggressive tumor with limited therapeutic options. We report a case of a malignant peritoneal mesothelioma (MPM) epithelioid type, with environmental asbestos exposure, in a 36-year-old man, with a long survival (17 years). The patient received standard treatment which included cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS AND RESULTS: Molecular analysis with comparative genomic hybridization (CGH)-array was performed on paraffin-embedded tumoral samples. Multiple chromosomal imbalances were detected. The gains were prevalent. Losses at 1q21, 2q11.1→q13, 8p23.1, 9p12→p11, 9q21.33→q33.1, 9q12→q21.33, and 17p12→p11.2 are observed. Chromosome band 3p21 (BAP1), 9p21 (CDKN2A) and 22q12 (NF2) are not affected. Conclusions: the defects observed in this case are uncommon in malignant peritoneal mesothelioma. Some chromosomal aberrations that appear to be random here, might actually be relevant events explaining the response to therapy, the long survival and, finally, may be considered useful prognostic factors in peritoneal malignant mesothelioma (PMM).


Assuntos
Amianto/efeitos adversos , Exposição Ambiental , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Mesotelioma/diagnóstico , Mesotelioma/etiologia , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/etiologia , Adulto , Biópsia , Hibridização Genômica Comparativa , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma Maligno
14.
Am J Med Genet A ; 170(7): 1884-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27148860

RESUMO

Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder whose associated phenotype is heterogeneous, depending on the size, and, mostly, on the deleted region. We report the clinical and molecular characterization of a female newborn, whose phenotype was characterized by poor growth, dysmorphic facial features, subclinical hypothyroidism, and mild reduction of CD3CD8 Lymphocytes with increased CD4/CD8 ratio. By array-CGH, we identified a 4.08 de novo interstitial deletion of the 14q13.2q21.1 region, which includes 16 OMIM genes.Our patient phenotype is compared with other published cases, for a better classification of the 14q11-q22 deletion syndrome. We demonstrated that the 14q13.2q21.1 deletion, which encompasses NKX2-1, but not FOXG1 gene and HPE8 region, identifies a well defined, more benign, microdeletion syndrome. This report confirms that an early identification with accurate characterization of the genomic disorders is of great relevance, enabling proper genetic counseling of the reproductive risk, as well as disease prognosis, and patient management. © 2016 Wiley Periodicals, Inc.


Assuntos
Deleção Cromossômica , Fatores de Transcrição Forkhead/genética , Hipotireoidismo/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Cromossomos Humanos Par 14/genética , Hibridização Genômica Comparativa , Face/fisiopatologia , Feminino , Humanos , Hipotireoidismo/fisiopatologia , Hibridização in Situ Fluorescente , Recém-Nascido , Linfócitos/patologia , Masculino , Fenótipo , Fator Nuclear 1 de Tireoide
15.
Nature ; 463(7282): 775-80, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-20148032

RESUMO

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Insulina/biossíntese , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Análise Mutacional de DNA , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Diabetes Mellitus/congênito , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Embrião de Mamíferos/metabolismo , Feminino , Feto/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genes Recessivos/genética , Testes Genéticos , Humanos , Recém-Nascido , Ilhotas Pancreáticas/embriologia , Masculino , Camundongos , Células NIH 3T3 , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Especificidade de Órgãos , Fatores de Transcrição de Fator Regulador X , Síndrome , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
16.
J Med Genet ; 52(12): 804-14, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26424144

RESUMO

BACKGROUND: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified. METHODS: We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported. RESULTS: The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations. CONCLUSIONS: In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.


Assuntos
Anormalidades Múltiplas/genética , Proteínas Nucleares/genética , Síndrome de Smith-Magenis/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Anormalidades Craniofaciais/genética , Feminino , Retardo do Crescimento Fetal/genética , Estudos de Associação Genética , Haploinsuficiência , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Convulsões/genética , Índice de Gravidade de Doença , Síndrome , Adulto Jovem
17.
Clin Immunol ; 161(2): 355-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26499378

RESUMO

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.


Assuntos
Arteriosclerose/genética , Síndromes de Imunodeficiência/genética , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Embolia Pulmonar/genética , Receptores de Interleucina-7/genética , Linfócitos T/metabolismo , Adolescente , Adulto , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Células Cultivadas , Criança , Pré-Escolar , DNA Helicases/genética , Metilação de DNA , Citometria de Fluxo , Expressão Gênica , Humanos , Imuno-Histoquímica , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Interleucina-17/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Mutação , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Doenças da Imunodeficiência Primária , Regiões Promotoras Genéticas/genética , Embolia Pulmonar/metabolismo , Embolia Pulmonar/patologia , Receptores de Interleucina-7/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Adulto Jovem
18.
Psychopathology ; 48(6): 417-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26609890

RESUMO

BACKGROUND: Previous studies have shown that alexithymia is associated with gene polymorphisms that regulate the availability of serotonin (5-HT) in the brain. Since the 5-HT network is involved in interferon (IFN)-induced depression, this paper aimed to investigate the role of alexithymia and the functional gene variants of the 5-HT1A receptor (HTR1A) and the 5-HT transporter (5-HTTLPR) in induction of depression during antiviral treatment. METHODS: The depressive symptoms of 130 consecutive patients with chronic hepatitis C and no current psychopathology were measured during treatment with IFN and ribavirin (6-12 months) and at a 6-month follow-up. At baseline, alexithymia and 2 genotypes (5-HTTLPR and HTR1A) were also assessed. RESULTS: Patients with homozygosity for HTR1A-G and 5-HTTLPR long alleles had significantly higher levels of alexithymia. After controlling for sociodemographic and disease-related factors, alexithymia and HTR1A-G polymorphism, both separately (20-22%) and jointly (14-16%), significantly and independently predicted the development of IFN-induced depression. CONCLUSIONS: Subjects carrying HTR1A-G and 5-HTTLRP double long alleles are more vulnerable to alexithymia. Also patients with a higher level of alexithymia and the HTR1A-G gene variant are more vulnerable to experiencing IFN-induced depressive symptoms. The clinical implications of targeting alexithymia and HTR1A receptors as a possible treatment option for mood disorders should be investigated in further studies.


Assuntos
Sintomas Afetivos/genética , Antivirais/efeitos adversos , Depressão/induzido quimicamente , Depressão/genética , Interferon-alfa/efeitos adversos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Antivirais/uso terapêutico , Feminino , Genótipo , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
19.
Eur J Pediatr ; 173(3): 277-83, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24464091

RESUMO

UNLABELLED: Abnormalities of the sex chromosomes (47, XXY, 47 XYY, 45,X/46,XY mosaicism) are frequently associated with Autism Spectrum Disorders (ASD), but the male predisposition to these disorders has not been clearly explained. Previously, the role of the X chromosome was considered important in the ASD mainly because autistic symptoms were detected in genetic syndromes involving X chromosome (fragile X syndrome, Rett syndrome, Klinefelter syndrome). Instead, few studies have analyzed the possible role of the Y chromosome in the ASD. This study explores the role of the Y chromosome in ASD through a systematic literature review about the association between ASD and XYY syndrome and a description of two new cases with this association. The literature review considered studies published in peer-reviewed journals, included in the MEDLINE and PubMed databases, that examined the association between ASD and XYY syndrome. Few studies reported the occurrence of ASD in children with XYY karyotype and the majority of them did not reported a well-defined autism diagnostic category associated with an extra Y chromosome, but several clinical conditions that are generically described as language and social impairment. CONCLUSION: This study underlines the underestimated role of the Y chromosome in ASD, and we postulate that all the ASD associated with the XYY karyotype may presumably fall within mild degree of ASD as in our cases.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais , Cariótipo XYY , Pré-Escolar , Humanos , Masculino
20.
BMC Pediatr ; 14: 220, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25182979

RESUMO

BACKGROUND: Microphthalmia with linear skin defects (MLS) syndrome is a rare X-linked dominant male-lethal developmental disorder characterized by unilateral or bilateral microphthalmia and linear skin defects of the face and neck. Additional features affecting the eyes, heart, brain or genitourinary system can occur, corroborating the intra- and interfamilial phenotypic variability. The majority of patients display monosomy of the Xp22.2 region, where the holocytochrome c-type synthase (HCCS) gene is located. CASE PRESENTATION: We describe a 15-year-old-female affected by MLS syndrome and autism spectrum disorder (ASD). ASD has not previously been reported as a component of MLS. Our patient shows a large deletion of 12.9 Mb, involving Xp22.32-p22.2, which encompasses both the HCCS gene and autism X-linked genes. CONCLUSION: Thus, patients with a large deletion at Xp22 might display MLS with ASD, due to the deletion of contiguous genes, although the highly variable phenotype of these patients could be influenced by several genetic mechanisms, including different tissue-specific X-inactivation and somatic mosaicism.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/etiologia , Cromossomos Humanos X , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Microftalmia/diagnóstico , Anormalidades da Pele/diagnóstico , Adolescente , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Microftalmia/complicações , Microftalmia/genética , Anormalidades da Pele/complicações , Anormalidades da Pele/genética
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