Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Brain ; 143(1): 55-68, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834374

RESUMO

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

3.
Med Princ Pract ; 29(1): 6-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31158841

RESUMO

OBJECTIVE: This study aims to present the diagnostic characteristics of multimodal intraoperative monitoring (IOM) in spinal deformity surgery and to define and categorise the neuromonitoring events, as well as propose an algorithm of action. MATERIALS AND METHODS: We reviewed 1,155 consecutive patients (807 female, 348 male) who underwent deformity correction using standardised perioperative care, cortical/cervical somatosensory evoked potentials (SSEPs), and upper/lower limb transcranial electrical motor evoked potential (MEPs) by a single surgeon. The mean age at surgery was 13.8 years (range 10-23.3). We categorised IOM events as true, transient true, and false positive or negative. Diagnostic performance criteria were calculated. RESULTS: The most common diagnosis was adolescent idiopathic scoliosis in 717 (62%) patients. We identified 3 true positive monitoring events occurring in 2 patients (0.17%), 8 transient true positive (0.69%), and 8 transient false positive events (0.69%). There were no false negative events and no patient had postoperative neurological complications. The multimodal IOM technique had a sensitivity of 100%, specificity of 99.3%, positive predictive value of 55.6%, and negative predictive value of 100%. Sensitivity was 100% for MEPs and multimodal monitoring compared to 20% for cortical or cervical SSEPs. The frequency of true or transient true positive events was higher (p = 0.07) in Scheuermann's kyphosis (3/91 patients, 3.3%) compared to adolescent idiopathic scoliosis (6/717 patients, 0.84%). CONCLUSION: Multimodal IOM is highly sensitive and specific for spinal cord injury. This technique is reliable for the assessment of the condition of the spinal cord during major deformity surgery. We propose an algorithm of intraoperative action to allow close cooperation between the surgical, anaesthetic, and neurophysiology teams and to prevent neurological deficits.

4.
Brain ; 142(10): 2948-2964, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501903

RESUMO

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

6.
Behav Brain Sci ; 42: e51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940279

RESUMO

Anselme & Güntürkün propose a novel mechanism to explain the increase in foraging motivation when experiencing an unpredictable food supply. However, the physiological mechanisms that maintain energy homeostasis already control foraging intensity in response to changes in energy balance. Therefore, unpredictability may just be one of many factors that feeds into the same dopaminergic "wanting" system to control foraging intensity.


Assuntos
Metabolismo Energético , Motivação , Incerteza
7.
Clin Transl Sci ; 12(3): 312-320, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30821933

RESUMO

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype-phenotype relationships were assessed by multivariate regression analysis, adjusted for self-reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 -1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e-05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self-reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.

8.
Am J Hum Genet ; 104(3): 542-552, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827498

RESUMO

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.


Assuntos
Motivos de Aminoácidos/genética , Variação Genética , Proteínas do Tecido Nervoso/genética , Transtornos Neurocognitivos/etiologia , Sequências Repetitivas de Ácido Nucleico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos Neurocognitivos/classificação , Transtornos Neurocognitivos/patologia , Fenótipo , Prognóstico , Síndrome
10.
Am J Hum Genet ; 103(5): 786-793, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343942

RESUMO

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.

11.
Orphanet J Rare Dis ; 13(1): 86, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-30012219

RESUMO

BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.


Assuntos
Adenosina Trifosfatases/genética , Disfunção Cognitiva/genética , Hipotonia Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Proteínas de Transferência de Fosfolipídeos/genética , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Humanos , Imagem por Ressonância Magnética , Hipotonia Muscular/etiologia , Atrofia Óptica/etiologia , Sequenciamento Completo do Exoma
12.
Proc Biol Sci ; 285(1879)2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29794047

RESUMO

In birds little is known about the hormonal signals that communicate nutritional state to the brain and regulate appetitive behaviours. In mammals, the peptide hormones ghrelin and leptin elevate and inhibit consumption and food hoarding, respectively. But in birds, administration of both ghrelin and leptin inhibit food consumption. The role of these hormones in the regulation of food hoarding in avian species has not been examined. To investigate this, we injected wild caught coal tits (Periparus ater) with leptin, high-dose ghrelin, low-dose ghrelin and a saline control in the laboratory. We then measured food hoarding and mass gain, as a proxy of food consumption, every 20 min for 2 h post-injection. Both high-dose ghrelin and leptin injections significantly reduced hoarding and mass gain compared with controls. Our results provide the first evidence that hoarding behaviour can be reduced by both leptin and ghrelin in a wild bird. These findings add to evidence that the hormonal control of food consumption and hoarding in avian species differs from that in mammals. Food hoarding and consumptive behaviours consistently show the same response to peripheral signals of nutritional state, suggesting that the hormonal regulation of food hoarding has evolved from the consumption regulatory system.


Assuntos
Ingestão de Alimentos , Grelina/farmacologia , Leptina/farmacologia , Aves Canoras/fisiologia , Ganho de Peso , Animais , Comportamento Apetitivo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Grelina/administração & dosagem , Injeções Intramusculares/veterinária , Leptina/administração & dosagem , Músculos Peitorais , Ganho de Peso/efeitos dos fármacos
13.
Ann Neurol ; 83(6): 1089-1095, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29518281

RESUMO

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.


Assuntos
Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Espasticidade Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Proteínas/genética , Ataxias Espinocerebelares/genética , Gânglios da Base/patologia , Encéfalo/patologia , Criança , Humanos , Doença de Leigh/patologia , Imagem por Ressonância Magnética/métodos , Espasticidade Muscular/patologia , Linhagem
14.
Cell ; 172(5): 924-936.e11, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474920

RESUMO

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.


Assuntos
Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Haploinsuficiência/genética , Mutação/genética , Proteínas de Ligação a RNA/genética , Convulsões/genética , Adolescente , Adulto , Idade de Início , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Evolução Molecular , Feminino , Deleção de Genes , Células HEK293 , Humanos , Lactente , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Estabilidade Proteica , Convulsões/diagnóstico por imagem
15.
Am J Hum Genet ; 102(2): 309-320, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29394990

RESUMO

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Heterogeneidade Genética , Atrofia Muscular/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Síndrome de Noonan/genética , Proteína cdc42 de Ligação ao GTP/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Masculino , Modelos Moleculares , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Síndrome de Noonan/metabolismo , Síndrome de Noonan/patologia , Fenótipo , Estrutura Secundária de Proteína , Índice de Gravidade de Doença , Proteína cdc42 de Ligação ao GTP/química , Proteína cdc42 de Ligação ao GTP/metabolismo
16.
J Pers Med ; 8(1)2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29389890

RESUMO

Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy.

17.
J Med Genet ; 55(8): 561-566, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28866611

RESUMO

BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.


Assuntos
Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Criança , Pré-Escolar , DNA Helicases/química , Proteínas de Ligação a DNA/química , Deficiências do Desenvolvimento/diagnóstico , Facies , Feminino , Fibroblastos/metabolismo , Estudos de Associação Genética/métodos , Histonas/metabolismo , Humanos , Lactente , Modelos Moleculares , Fenótipo , Conformação Proteica , Relação Estrutura-Atividade
18.
PeerJ ; 5: e3883, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29018617

RESUMO

In freshwater environments, chemosensory cues play an important role in predator-prey interactions. Prey use a variety of chemosensory cues to detect and avoid predators. However, whether predators use the chemical cues released by disturbed or stressed prey has received less attention. Here we tested the hypothesis that the disturbance cue cortisol, in conjunction with visual cues of prey, elevates predatory behavior. We presented predators (perch, Perca fluviatilis) with three chemosensory choice tests and recorded their location, orientation, and aggressive behavior. We compared the responses of predators when provided with (i) visual cues of prey only (two adjacent tanks containing sticklebacks); (ii) visual and natural chemical cues of prey vs. visual cues only; and (iii) visual cues of prey with cortisol vs. visual cues only. Perch spent a significantly higher proportion of time in proximity to prey, and orientated toward prey more, when presented with a cortisol stimulus plus visual cues, relative to presentations of visual and natural chemical cues of prey, or visual cues of prey only. There was a trend that perch directed a higher proportion of predatory behaviors (number of lunges) toward sticklebacks when presented with a cortisol stimulus plus visual cues, relative to the other chemosensory conditions. But they did not show a significant increase in total predatory behavior in response to cortisol. Therefore, it is not clear whether water-borne cortisol, in conjunction with visual cues of prey, affects predatory behavior. Our results provide evidence that cortisol could be a source of public information about prey state and/or disturbance, but further work is required to confirm this.

19.
Ann Neurol ; 82(3): 466-478, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28856709

RESUMO

OBJECTIVE: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions. METHODS: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models. RESULTS: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. INTERPRETATION: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.


Assuntos
Mutação , Receptores de GABA-B/genética , Síndrome de Rett/genética , Espasmos Infantis/genética , Exoma , Genótipo , Células HEK293 , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo , Transdução de Sinais/genética
20.
Eur J Hum Genet ; 25(8): 946-951, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28513610

RESUMO

The introduction of whole-exome sequencing into the Pediatric Genetics clinic has increased the identification of novel genes associated with neurodevelopmental disorders and congenital anomalies. This agnostic approach has shed light on multiple proteins and pathways not previously known to be associated with disease. Here we report eight subjects from six families with predicted loss of function variants in ZNF462, a zinc-finger protein of unknown function. These individuals have overlapping phenotypes that include ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay. We propose that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.


Assuntos
Agenesia do Corpo Caloso/genética , Blefaroptose/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Adulto , Agenesia do Corpo Caloso/diagnóstico , Blefaroptose/diagnóstico , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Lactente , Masculino , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA