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In the Netherlands, patients who have a life expectancy of less than three months may be admitted to a hospice. In a small number of patients, however, their life expectancy is underestimated. It is assumed that patients are delighted to have this extra time. We present the cases of three patients admitted to a large Dutch hospice: two females aged 82 and 83 years, and a 49-year-old man -who ended up living (significantly) longer than expected. Their cases make clear that patients in this situation may suffer from psychological, psychosocial, and existential distress. We argue that it is important that patients and their relatives are informed about their life expectancy, but that uncertainty in the estimation of said expectancy should be emphasized.
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Cuidados Paliativos na Terminalidade da Vida/psicologia , Expectativa de Vida , Estresse Psicológico/etiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países BaixosRESUMO
Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.
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Canais de Cloreto/genética , Síndromes Epilépticas/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Canais de Cloreto/metabolismo , Epilepsia/genética , Síndromes Epilépticas/fisiopatologia , Família , Feminino , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Humanos , Deficiência Intelectual/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Oócitos , Linhagem , Fenótipo , Síndrome , Substância Branca/fisiopatologia , Xenopus laevisRESUMO
INTRODUCTION: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. AREAS COVERED: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). EXPERT OPINION: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.
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Haloperidol/administração & dosagem , Midazolam/administração & dosagem , Morfina/administração & dosagem , Cuidados Paliativos/métodos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Haloperidol/farmacocinética , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacocinética , Midazolam/farmacocinética , Morfina/farmacocinética , Qualidade de Vida , Assistência Terminal/métodosRESUMO
The megavolt ITER injector and concept advancement experiment is the prototype and the test bed of the ITER heating and current drive neutral beam injectors, currently in the final design phase, in view of the installation in Padova Research on Injector Megavolt Accelerated facility in Padova, Italy. The beam source is the key component of the system, as its goal is the generation of the 1 MeV accelerated beam of deuterium or hydrogen negative ions. This paper presents the highlights of the latest developments for the finalization of the MITICA beam source design, together with a description of the most recent analyses and R&D activities carried out in support of the design.
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X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
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Variação Genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Animais , Células Cultivadas , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Estudos de Coortes , Quinases Ciclina-Dependentes/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histona Acetiltransferases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/genética , RNA Mensageiro/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Non-invasive prenatal testing (NIPT) for fetal aneuploidy detection is increasingly being offered in the clinical setting. Whereas the majority of tests only report fetal trisomies 21, 18 and 13, genome-wide analyses have the potential to detect other fetal, as well as maternal, aneuploidies. In this review, we discuss the technical and clinical advantages and challenges associated with genome-wide cell-free fetal DNA profiling.
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Aneuploidia , DNA/genética , Doenças Fetais/diagnóstico , Diagnóstico Pré-Natal/métodos , Feminino , Doenças Fetais/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Gravidez , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.
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Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/fisiologia , Rede Nervosa/metabolismo , Diferenciação Celular , Dendritos/metabolismo , Dosagem de Genes/fisiologia , Duplicação Gênica/genética , Estudos de Associação Genética , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Neurogênese , NeurôniosRESUMO
Children with unexplained developmental disabilities or congenital anomalies are increasingly being referred for genetic diagnostic testing using array-comparative genomic hybridisation (array-CGH) and next-generation sequencing (NGS) technologies. Their parents will have to deal with the secondary variants that will inevitably arise. We conducted 16 prospective semi-structured interviews with native Dutch-speaking parents whose children had undergone clinical array-CGH testing. The interviews explored the parents' experiences, expectations and opinions, specifically regarding the communication of results. Concrete examples of 'unexpected results' were provided to help guide the discussion, differing in severity, treatability, time of onset, level of risk, and carrier status. Data was analysed using content and narrative analysis methodologies. Parental motivations for and against the disclosure of unexpected results cluster around four main themes: actionability; knowledge; context; and characteristics of the result. Most parents wished to know all types of results. Disclosure was framed within a holistic, contextual, family-wide view. Genetic counselling should aim to integrate explorations of the motivations of parents surrounding the disclosure of results with good clinical care.
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Hibridização Genômica Comparativa/métodos , Revelação , Aconselhamento Genético/métodos , Predisposição Genética para Doença/genética , Achados Incidentais , Pais/psicologia , Adulto , Criança , Aconselhamento Genético/psicologia , Humanos , Entrevistas como Assunto , Países Baixos , Estudos ProspectivosRESUMO
The 22q13 deletion syndrome is characterised by intellectual disability (ID), delayed or absent speech, autistic-like behaviour and minor, nonspecific dysmorphic features. The deletion of the SHANK3 gene is thought to be responsible for these features. In this study, the clinical data of 7 patients with the 22q13 deletion syndrome are presented, obtained by clinical genetic examination, direct behavioural observation and by interview of family members and/or caregivers, complemented by behavioural questionnaires. The specific focus was on behaviour, psychopathology and the level of functioning during life course in order to determine common features that might contribute to the delineation of the syndrome. Major findings were a high incidence of psychiatric disorders, more in particular bipolar disorder (BPD) and attention deficit hyperactivity disorder (ADHD), and a sudden deterioration after acute events, in addition to a progressive loss of skills over years. Therefore, a deletion of SHANK3 may result in a dysfunctional nervous system, more susceptible to developmental problems and psychiatric disorders on the one hand, less able to recuperate after psychiatric and somatic events, and more vulnerable to degeneration at long term on the other hand. These results are exploratory and need to be confirmed in a larger sample.
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Microduplication 22q11.2 is a recently discovered genomic disorder. So far, targeted research on the cognitive and behavioral characteristics of individuals with this microduplication is limited. Therefore, 11 Flemish children (3-13 years old) with a microduplication 22q 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their general intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.11.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip, feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype.
Assuntos
Síndrome da Deleção 22q11/diagnóstico , Síndrome da Deleção 22q11/psicologia , Anormalidades Múltiplas/diagnóstico , Transtornos do Comportamento Infantil/diagnóstico , Transtornos Cognitivos/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Duplicação Gênica , Síndrome da Deleção 22q11/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Atenção , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Bélgica , Criança , Comportamento Infantil/psicologia , Transtornos do Comportamento Infantil/genética , Transtornos do Comportamento Infantil/psicologia , Desenvolvimento Infantil , Pré-Escolar , Cromossomos Humanos Par 22/genética , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/psicologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/psicologia , Masculino , Desempenho PsicomotorRESUMO
Genome-wide array comparative genome hybridization has become the first in line diagnostic tool in the clinical work-up of patients presenting with intellectual disability. As a result, chromosome X-copy number variations are frequently being detected in routine diagnostics. We retrospectively reviewed genome wide array-CGH data in order to determine the frequency and nature of chromosome X-copy number variations (X-CNV) in a cohort of 2222 sporadic male patients with intellectual disability (ID) referred to us for diagnosis. In this cohort, 68 males were found to have at least one X-CNV (3.1%). However, correct interpretation of causality remains a challenging task, and is essential for proper counseling, especially when the CNV is inherited. On the basis of these data, earlier experience and literature data we designed and propose an algorithm that can be used to evaluate the clinical relevance of X-CNVs detected in sporadic male ID patients. Applied to our cohort, 19 male ID patients (0.85%) were found to carry a (likely) pathogenic X-CNV.
Assuntos
Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Aconselhamento Genético , Loci Gênicos , Genoma Humano , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Since the initial report that clearly established a causal role between duplication of the MECP2 gene and a severe syndromic form of intellectual disability, many new patients have been identified and reported, and the etiology in already published families solved. This has led to the establishment of a clinically recognizable disorder. Here, we review the clinical data of 129 reported and nonreported male patients with MECP2 duplication syndrome.
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In a multi-aperture multi-grid accelerator of the ITER neutral beam injector, the beamlets are deflected due to space charge repulsion between beamlets and beam groups, and also due to magnetic field. Moreover, the beamlet deflection is influenced by electric field distortion generated by grid support structure. Such complicated beamlet deflections and the compensations have been examined utilizing a three-dimensional beam analysis. The space charge repulsion and the influence by the grid support structure were studied in a 1∕4 model of the accelerator including 320 beamlets. Beamlet deflection due to the magnetic field was studied by a single beamlet model. As the results, compensation methods of the beamlet deflection were designed, so as to utilize a metal bar (so-called field shaping plate) of 1 mm thick beneath the electron suppression grid (ESG), and an aperture offset of 1 mm in the ESG.
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We identified a male patient presenting with intellectual disability and agenesis of the corpus callosum, carrying an apparently balanced, reciprocal, de novo translocation t(6;14)(q25.3;q13.2). Breakpoint mapping, using array painting, identified 2 interesting candidate genes, ARID1B and MRPP3, disrupted in the patient. Unexpectedly, the rearrangement produced 3 in-frame reciprocal fusion transcripts that were further characterized. Formation of fusion transcripts is mainly reported in acquired malignancies and is very rarely observed in patients with intellectual disability (ID) and/or multiple congenital malformations (MCA). Additional experimental results suggest that ARID1B, a gene involved in chromatin remodeling, constitutes a good candidate for the central nervous system phenotype present in the patient.
Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso , Deficiência Intelectual/patologia , Translocação Genética , Anormalidades Múltiplas/patologia , Adolescente , Sequência de Bases , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Fusão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants with myriad biological effects, including carcinogenicity. We present data showing gender-specific genotoxicity in Fischer 344 transgenic BigBlue rodents exposed to 4-chlorobiphenyl (PCB3), a hydroxylated metabolite, and the positive control 3-methylcholanthrene (3-MC) where female rats are more resistant to the genotoxic effects of the test compounds compared to their male counterparts. This difference is further highlighted through our examination of gene expression, organ-specific weight changes, and tissue morphology. The purpose of the present study was to explore the complex and multifaceted issues of lower molecular weight PCBs as initiators of carcinogenesis, by examining the mutagenicity of PCB3, a hydroxylated metabolite (4'-OH-PCB3), and 3-methylcholanthrene (3-MC, positive control) in a transgenic rodent model. Previous findings indicated that PCB3 is mutagenic in the liver of male BigBlue transgenic rats under identical exposure conditions. We expected that female rats would be equally, if not more sensitive than male rats, since a 2-year carcinogenesis bioassay with Sprague-Dawley rats and commercial PCB mixtures reported much higher liver cancer rates in female than in male rats. The current study, however, revealed a similar trend in the mutation frequencies across all four treatment groups in females as reported previously in males, but increased variability among animals within each group and a lower overall effect, led to non significant differences in mutation frequencies. A closer analysis of the possible reasons for this negative result using microarray, organ weight and histology data comparisons shows that female Fischer 344 rats 1) had a higher baseline mutation frequency in the corn oil control group and greater variability than male rats; 2) responded with robust gene expression changes, which may also play a role in our observation of 3) highly increased liver, spleen, and lung weight in 3-MC and PCB3-treated female rats and thus changed distribution and kinetics of the test compounds. Our analysis indicates that female transgenic BigBlue Fischer 344 rats are more resistant to PCB3 and 3-MC genotoxicity compared to their male counterparts.
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Compostos de Bifenilo/toxicidade , Metilcolantreno/toxicidade , Mutagênicos/toxicidade , Caracteres Sexuais , Animais , Feminino , Perfilação da Expressão Gênica , Histocitoquímica , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Análise em Microsséries , Mutação , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Baço/efeitos dos fármacos , Baço/patologiaRESUMO
Recently, submicroscopic deletions of the 5q14.3 region have been described in patients with severe mental retardation (MR), stereotypic movements, epilepsy and cerebral malformations. Further delineation of a critical region of overlap in these patients pointed to MEF2C as the responsible gene. This finding was further reinforced by the identification of a nonsense mutation in a patient with a similar phenotype. In brain, MEF2C is essential for early neurogenesis, neuronal migration and differentiation. Here we present two additional patients with severe MR, autism spectrum disorder and epilepsy, carrying a very small deletion encompassing the MEF2C gene. This finding strengthens the role of this gene in severe MR, and enables further delineation of the clinical phenotype.
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Proteínas de Domínio MADS/genética , Fatores de Regulação Miogênica/genética , Adolescente , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Epilepsias Mioclônicas/genética , Haploinsuficiência , Humanos , Lactente , Deficiência Intelectual/genética , Fatores de Transcrição MEF2 , Masculino , Fenótipo , Deleção de SequênciaRESUMO
This paper describes the physics design of a 100 keV, 60 A H(-) accelerator for the diagnostic neutral beam (DNB) for international tokamak experimental reactor (ITER). The accelerator is a three grid system comprising of 1280 apertures, grouped in 16 groups with 80 apertures per beam group. Several computer codes have been used to optimize the design which follows the same philosophy as the ITER Design Description Document (DDD) 5.3 and the 1 MeV heating and current drive beam line [R. Hemsworth, H. Decamps, J. Graceffa, B. Schunke, M. Tanaka, M. Dremel, A. Tanga, H. P. L. De Esch, F. Geli, J. Milnes, T. Inoue, D. Marcuzzi, P. Sonato, and P. Zaccaria, Nucl. Fusion 49, 045006 (2009)]. The aperture shapes, intergrid distances, and the extractor voltage have been optimized to minimize the beamlet divergence. To suppress the acceleration of coextracted electrons, permanent magnets have been incorporated in the extraction grid, downstream of the cooling water channels. The electron power loads on the extractor and the grounded grids have been calculated assuming 1 coextracted electron per ion. The beamlet divergence is calculated to be 4 mrad. At present the design for the filter field of the RF based ion sources for ITER is not fixed, therefore a few configurations of the same have been considered. Their effect on the transmission of the electrons and beams through the accelerator has been studied. The OPERA-3D code has been used to estimate the aperture offset steering constant of the grounded grid and the extraction grid, the space charge interaction between the beamlets and the kerb design required to compensate for this interaction. All beamlets in the DNB must be focused to a single point in the duct, 20.665 m from the grounded grid, and the required geometrical aimings and aperture offsets have been calculated.
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Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
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Transtorno Autístico/genética , Códon sem Sentido/genética , Deficiência Intelectual/genética , Neurônios/metabolismo , Proteínas de Ligação a RNA/genética , Adulto , Substituição de Aminoácidos/genética , Animais , Transtorno Autístico/complicações , Linhagem Celular , Espinhas Dendríticas/metabolismo , Regulação para Baixo , Feminino , Hipocampo/metabolismo , Humanos , Deficiência Intelectual/complicações , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Estabilidade de RNA , Proteínas de Ligação a RNA/metabolismoRESUMO
Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.
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Hipoplasia Dérmica Focal/genética , Proteínas de Membrana/genética , Mutação/genética , Aciltransferases , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana/química , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genéticaRESUMO
Low frequency (<100 Hz) downsweep vocalizations were repeatedly recorded from ocean gliders east of Cape Cod, MA in May 2005. To identify the species responsible for this call, arrays of acoustic recorders were deployed in this same area during 2006 and 2007. 70 h of collocated visual observations at the center of each array were used to compare the localized occurrence of this call to the occurrence of three baleen whale species: right, humpback, and sei whales. The low frequency call was significantly associated only with the occurrence of sei whales. On average, the call swept from 82 to 34 Hz over 1.4 s and was most often produced as a single call, although pairs and (more rarely) triplets were occasionally detected. Individual calls comprising the pairs were localized to within tens of meters of one another and were more similar to one another than to contemporaneous calls by other whales, suggesting that paired calls may be produced by the same animal. A synthetic kernel was developed to facilitate automatic detection of this call using spectrogram-correlation methods. The optimal kernel missed 14% of calls, and of all the calls that were automatically detected, 15% were false positives.