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










Base de dados
Intervalo de ano de publicação
1.
Hum Mol Genet ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073849

RESUMO

MPP5 is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD), and compared their phenotypes and MRIs to ascertain how MPP5 DNV lead to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRIs ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on developing brain was assessed by creating a heterozygous (het) murine model with CNS-specific nestin-Cre drivers (het CKO). In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared to wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.

2.
Orphanet J Rare Dis ; 15(1): 294, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33076953

RESUMO

BACKGROUND: MAGEL2-associated Schaaf-Yang syndrome (SHFYNG, OMIM #615547, ORPHA: 398069), which was identified in 2013, is a rare disorder caused by truncating variants of the paternal copy of MAGEL2, which is localized in the imprinted region on 15q11.2q13. The phenotype of SHFYNG in childhood partially overlaps with that of the well-established Prader-Willi syndrome (PWS, OMIM #176270). While larger numbers of younger individuals with SHFYNG have been recently published, the phenotype in adulthood is not well established. We recruited 7 adult individuals (aged 18 to 36) with molecularly confirmed SHFYNG and collected data regarding the clinical profile including eating habits, sleep, behavior, personal autonomy, psychiatric abnormalities and other medical conditions, as well as information about the respective phenotypes in childhood. RESULTS: Within our small cohort, we identified a range of common features, such as disturbed sleep, hypoactivity, social withdrawal and anxiety, but also noted considerable differences at the level of personal autonomy and skills. Behavioral problems were frequent, and a majority of individuals displayed weight gain and food-seeking behavior, along with mild intellectual disability or borderline intellectual function. Classical symptoms of SHFYNG in childhood were reported for most individuals. CONCLUSION: Our findings indicate a high variability of the functional abilities and social participation of adults with SHFYNG. A high prevalence of obesity within our cohort was notable, and uncontrollable food intake was a major concern for some caregivers. The phenotypes of PWS and SHFYNG in adulthood might be more difficult to discern than the phenotypes in childhood. Molecular genetic testing for SHFYNG should therefore be considered in adults with the suspected diagnosis of PWS, if testing for PWS has been negative.

4.
BMC Neurol ; 20(1): 121, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32252670

RESUMO

BACKGROUND: Spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord is better known as herniated spinal cord. There are many arguments in favour of considering it a developmental defect. From this point of view, it is a type of neural tube disorder. Neural tube disorders can be caused by multiple factors, including a genetic factor. A common genetic defect in patients with a spinal dysraphism with a hamartomatous growth of the spinal cord is sought for. CASE PRESENTATION: In two patients with a symptomatic lesion and referred to an academic hospital a genetic analysis was performed after informed consent. Whole-exome analysis was performed. : Whole-exome analysis did not result in identification of a clinically relevant genetic variant. CONCLUSIONS: This the first study to investigate the genetic contribution to spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord. We could not establish a genetic cause for this entity. This conclusion cannot be definitive due to the small sample size. However, the incidental occurrence, the lack of reports of inheritance of this disorder and the absence of contribution to syndromal disorders favours a defect of normal development of the spinal cord.

5.
Hum Mutat ; 41(1): 196-202, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31498527

RESUMO

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.

6.
Sci Adv ; 5(9): eaax2166, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31579823

RESUMO

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Variação Genética , Neurogênese/genética , Proteínas de Ligação a RNA/genética , Transmissão Sináptica/genética , Adolescente , Animais , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Camundongos , Neurônios/metabolismo , Linhagem , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Sinapses/genética , Sinapses/metabolismo , Adulto Jovem
9.
Am J Hum Genet ; 104(2): 203-212, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30612693

RESUMO

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Encéfalo/anormalidades , Encéfalo/metabolismo , Deficiência Intelectual/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Animais , Encéfalo/diagnóstico por imagem , Sistemas CRISPR-Cas , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Criança , Pré-Escolar , Simulação por Computador , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Locomoção , Lisossomos/metabolismo , Masculino , Modelos Moleculares , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
10.
Eur J Hum Genet ; 27(5): 738-746, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

11.
Eur J Med Genet ; 62(4): 265-269, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30125676

RESUMO

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p < 0.001) and PKD/IC in two (p = 0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes.


Assuntos
Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Adolescente , Adulto , Transtorno Autístico/patologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 16/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino
12.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.


Assuntos
DNA Helicases/genética , Deficiências do Desenvolvimento/genética , Transtornos da Linguagem/genética , Megalencefalia/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Domínios Proteicos/genética , Distúrbios da Fala/genética , Adenosina Trifosfatases , Pré-Escolar , Montagem e Desmontagem da Cromatina , Feminino , Expressão Gênica , Genótipo , Células HEK293 , Humanos , Deficiência Intelectual/genética , Masculino , Modelos Moleculares , Fenótipo , Sequenciamento Completo do Genoma
13.
Ann Neurol ; 84(5): 788-795, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30269351

RESUMO

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.


Assuntos
Proteínas de Transporte/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Criança , Pré-Escolar , Epilepsia Generalizada/genética , Feminino , Genótipo , Humanos , Masculino , Mutação , Fenótipo
15.
Ann Neurol ; 84(2): 200-207, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30014507

RESUMO

OBJECTIVE: Developmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology. METHODS: We clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER. RESULTS: All 9 individuals harbored heterozygous null-allele variants in CUX1, encoding the Cut-homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age-related intelligence at ages 4, 6, and 8 years after a previous history of significant DD. INTERPRETATION: Our results suggest that null-allele variants, and thus haploinsufficiency of CUX1, cause an isolated phenotype of DD or ID with possible catch-up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200-207.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adulto , Criança , Pré-Escolar , Feminino , Variação Genética/genética , Humanos , Masculino , Fatores de Transcrição
16.
Hum Mol Genet ; 27(16): 2775-2788, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29741626

RESUMO

Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation in MMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murine MMP14 mutations, does not affect MMP14's transport to the cell membrane. Instead, it partially impairs MMP14's proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14's catalytic activity is the prime determinant of disease severity. Given the limitations of our in vitro assays in addressing the consequences of MMP14 dysfunction, we generated a novel mmp14a/b knockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.


Assuntos
Anormalidades Múltiplas/genética , Contratura/genética , Opacidade da Córnea/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Metaloproteinase 14 da Matriz/genética , Osteólise/genética , Osteoporose/genética , Anormalidades Múltiplas/fisiopatologia , Alelos , Animais , Domínio Catalítico/genética , Contratura/fisiopatologia , Opacidade da Córnea/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Técnicas de Inativação de Genes , Transtornos do Crescimento/fisiopatologia , Humanos , Camundongos , Osteólise/fisiopatologia , Osteoporose/fisiopatologia , Fenótipo , Peixe-Zebra
18.
J Med Genet ; 55(2): 104-113, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29097605

RESUMO

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.


Assuntos
Proteínas de Ligação a DNA/genética , Face/anormalidades , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/química , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Feminino , Estudos de Associação Genética , Humanos , Recém-Nascido , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Gravidez , Homologia Estrutural de Proteína , Síndrome , Fatores de Transcrição/química
19.
Am J Hum Genet ; 102(1): 44-57, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29276004

RESUMO

Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epilepsia/genética , Proteínas de Ligação ao GTP/genética , Mutação de Sentido Incorreto/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Sequência de Aminoácidos , Animais , Comportamento Animal , Criança , Pré-Escolar , Dendritos/metabolismo , Feminino , Proteínas de Ligação ao GTP/química , Dosagem de Genes , Células HEK293 , Humanos , Masculino , Fenótipo , Sinapses/patologia , Proteínas Supressoras de Tumor/química
20.
Am J Hum Genet ; 101(5): 716-724, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100085

RESUMO

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto/genética , RNA Helicases/genética , Adenosina Trifosfatases/genética , Adolescente , Aminoácidos/genética , Linhagem Celular , Linhagem Celular Tumoral , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/genética , Masculino , RNA/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA