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1.
BMC Pediatr ; 21(1): 384, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479510

RESUMO

BACKGROUND: The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl-/H+ exchanger ClC-4 prominently expressed in brain. CASE PRESENTATION: We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. CONCLUSION: Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.


Assuntos
Deficiência Intelectual , Retardo Mental Ligado ao Cromossomo X , Pré-Escolar , China , Canais de Cloreto/genética , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
2.
Nat Commun ; 12(1): 5253, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489471

RESUMO

Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.


Assuntos
Adipócitos/fisiologia , Elementos Facilitadores Genéticos , Pleiotropia Genética , Obesidade/genética , Adipócitos/citologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Estudo de Associação Genômica Ampla , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Hipotálamo/fisiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , MAP Quinase Quinase 5/genética , Neurônios/citologia , Neurônios/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/genética , Locos de Características Quantitativas , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Fatores de Transcrição/genética , Transcriptoma
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 779-782, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365624

RESUMO

OBJECTIVE: To explore the genetic basis for a child with febrile seizures. METHODS: Peripheral venous blood samples were taken from the child and his parents for the analysis of chromosomal karyotype and dynamic variant of the FMR1 gene. The family trio was also subjected to target capture and next generation sequencing (NGS) with a gene panel related to developmental retardation, mental retardation, language retardation, epilepsy and special facial features. RESULTS: The child was found to have a normal karyotype by conventional cytogenetic analysis (400 bands). No abnormal expansion was found with the CGG repeats of the FMR1 gene. NGS revealed that the child has carried a heterozygous c.864+1 delG variant of the MEF2C gene, which may lead to abnormal splicing and affect its protein function. The same variant was found in neither parent, suggesting that it has a de novo origin. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.864+1delG variant of MEF2C gene was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: MEF2C, as the key gene for chromosome 5q14.3 deletion syndrome which was speculated as a cause for febrile seizures, has an autosomal dominant effect. The c.864+1delG variant of the MEF2C gene may account for the febrile seizures in this patient.


Assuntos
Transtornos Cromossômicos , Epilepsia , Deficiência Intelectual , Criança , Deleção Cromossômica , Proteína do X Frágil de Retardo Mental , Humanos , Deficiência Intelectual/genética , Cariotipagem , Fatores de Transcrição MEF2/genética
4.
Am J Hum Genet ; 108(9): 1692-1709, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34375587

RESUMO

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.


Assuntos
Encéfalo/metabolismo , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Mutação , Receptores de Ácido Caínico/genética , Adolescente , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/metabolismo , Epilepsia/patologia , Potenciais Evocados/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Ativação do Canal Iônico , Masculino , Modelos Moleculares , Neurônios/metabolismo , Neurônios/patologia , Conformação Proteica , Receptores de Ácido Caínico/química , Receptores de Ácido Caínico/metabolismo
5.
Am J Hum Genet ; 108(9): 1710-1724, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450031

RESUMO

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.


Assuntos
Osso e Ossos/metabolismo , Complexo I de Proteína do Envoltório/genética , Proteína Coatomer/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Osteoporose/genética , Animais , Ácido Ascórbico/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Pré-Escolar , Complexo I de Proteína do Envoltório/deficiência , Proteína Coatomer/química , Proteína Coatomer/deficiência , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Embrião não Mamífero , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Complexo de Golgi , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Índice de Gravidade de Doença , Peixe-Zebra
6.
Cytogenet Genome Res ; 161(3-4): 153-159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229322

RESUMO

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the IQSEC2 gene in the girl, a variant that is related to X-linked intellectual disability.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Códon sem Sentido , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Pré-Escolar , Consanguinidade , Feminino , Genes Ligados ao Cromossomo X/genética , Homozigoto , Humanos , Cariotipagem , Telômero/genética , Sequenciamento Completo do Exoma
7.
Am J Hum Genet ; 108(9): 1669-1691, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34314705

RESUMO

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.


Assuntos
Deficiências do Desenvolvimento/genética , Proteínas de Drosophila/genética , Oftalmopatias Hereditárias/genética , Deficiência Intelectual/genética , Carioferinas/genética , Anormalidades Musculoesqueléticas/genética , beta Carioferinas/genética , Proteína ran de Ligação ao GTP/genética , Alelos , Sequência de Aminoácidos , Animais , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Feminino , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genoma Humano , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Carioferinas/antagonistas & inibidores , Carioferinas/metabolismo , Masculino , Anormalidades Musculoesqueléticas/metabolismo , Anormalidades Musculoesqueléticas/patologia , Mutação , Neurônios/metabolismo , Neurônios/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Sequenciamento Completo do Genoma , beta Carioferinas/metabolismo , Proteína ran de Ligação ao GTP/metabolismo
8.
Genes (Basel) ; 12(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200686

RESUMO

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the advent of whole exome sequencing, many NAA10 variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The NAA10 gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo NAA10 [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype-phenotype correlation in females with NAA10-related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Fenótipo , Adolescente , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Genótipo , Humanos , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto , Síndrome
9.
Genes (Basel) ; 12(6)2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205270

RESUMO

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Genótipo , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fenótipo , Anormalidades Múltiplas/patologia , Face/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Micrognatismo/patologia , Mutação , Pescoço/patologia , Fatores de Transcrição/genética
10.
Eur J Med Genet ; 64(9): 104289, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34265435

RESUMO

BACKGROUND: Kleefstra syndrome type 1 (KS1, OMIM#610253) is a rare autosomal-dominant Mendelian disorder due to heterozygous mutations in the EHMT1 gene or heterozygous deletion of genomic segment of 9q34.3(9qdel). Neurodevelopmental disorder (NDD), intellectual disability (ID) and childhood-onset hypotonia are the well-known phenotypes of KS1. However, these findings were all investigated based on western patients with KS1. METHODS: KS1 patients were diagnosed by genetic tests. The clinical data was collected and the phenotypes were standardized by compared with patients that previously reported. In silico, conservational and protein structural analysis were performed to assessment the missense variants. RESULTS: Ten patients from unrelated families were diagnosed as KS1, who all had NDD and seven of them had global developmental delay (GDD) with significant personal-social disabilities. Among the ten patients, only one (1/10) patient showed neonatal or infantile obesity. The other nine patients were heterozygous variations, including three missense mutations (p.Glu235Gly, p.Asp903Gly, and p.Leu943Pro), three frameshifting mutations (p.Asn1106Lysfs*71, p.Asn1055Tyrfs*121, and p.Lys288Argfs*20), one nonsense mutation (p.Arg246*), one slice site mutation (c.3540+2T > C) and one 9q34.3 deletion in gene of EHMT1. Furthermore, missense mutations showed potential pathogenicity analyzed by in silico. CONCLUSION: We demonstrated that the clinical features in Chinese patients with KS1 were due to EHMT1 defects. We also reported seven novel variants which enriched the mutation spectrum and provided a good understanding of the pathogenesis of KS1.


Assuntos
Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/patologia , Feminino , Cardiopatias Congênitas/patologia , Heterozigoto , Histona-Lisina N-Metiltransferase/química , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Mutação , Fenótipo , Domínios Proteicos
11.
Nat Commun ; 12(1): 4050, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193871

RESUMO

The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.


Assuntos
Anormalidades Múltiplas/patologia , Proteínas de Transporte/metabolismo , Anormalidades Craniofaciais/patologia , Dano ao DNA , Deformidades Congênitas da Mão/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Deficiência Intelectual/patologia , Mutação , Unhas Malformadas/patologia , Células-Tronco Neurais/patologia , Proteínas Nucleares/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Unhas Malformadas/genética , Unhas Malformadas/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas Nucleares/genética , Organoides
12.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199759

RESUMO

The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18, and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease.


Assuntos
Alelos , Deficiência Intelectual/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Canais de Potássio/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Calcineurina/metabolismo , Feminino , Genoma Humano , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Ionomicina/farmacologia , Masculino , Linhagem , Canais de Potássio/química , Irmãos , Xenopus laevis/metabolismo , Adulto Jovem
13.
J Cell Sci ; 134(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34228795

RESUMO

Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism and schizophrenia, have high socioeconomic impact, yet poorly understood etiologies. A recent surge of large-scale genome or exome sequencing studies has identified a multitude of mostly de novo mutations in subunits of the protein phosphatase 2A (PP2A) holoenzyme that are strongly associated with NDDs. PP2A is responsible for at least 50% of total Ser/Thr dephosphorylation in most cell types and is predominantly found as trimeric holoenzymes composed of catalytic (C), scaffolding (A) and variable regulatory (B) subunits. PP2A can exist in nearly 100 different subunit combinations in mammalian cells, dictating distinct localizations, substrates and regulatory mechanisms. PP2A is well established as a regulator of cell division, growth, and differentiation, and the roles of PP2A in cancer and various neurodegenerative disorders, such as Alzheimer's disease, have been reviewed in detail. This Review summarizes and discusses recent reports on NDDs associated with mutations of PP2A subunits and PP2A-associated proteins. We also discuss the potential impact of these mutations on the structure and function of the PP2A holoenzymes and the etiology of NDDs.


Assuntos
Deficiência Intelectual , Proteína Fosfatase 2 , Animais , Humanos , Deficiência Intelectual/genética , Mutação , Fosforilação , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Subunidades Proteicas/metabolismo
14.
BMC Psychiatry ; 21(1): 360, 2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273950

RESUMO

BACKGROUND: Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene. CASE PRESENTATION: The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant. CONCLUSIONS: The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Adolescente , Transtorno do Espectro Autista/genética , Proteínas do Citoesqueleto/genética , Feminino , Humanos , Deficiência Intelectual/genética , Pessoa de Meia-Idade , Fenótipo , Qualidade de Vida , Fatores de Transcrição/genética
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 565-568, 2021 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-34096027

RESUMO

OBJECTIVE: To explore the genetic basis for a child featuring global developmental delay. METHODS: DNA was extracted from peripheral blood sample taken from the patient and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing of his family members. RESULTS: A heterozygous c.239T>C (p.Ile80Thr) variant of the GNB1 gene was detected in the proband, which was a verified to be de novo in origin. CONCLUSION: The heterozygous c.239T>C (p.Ile80Thr) variant of the GNB1 gene probably underlay the disease in this child.


Assuntos
Artrogripose , Subunidades beta da Proteína de Ligação ao GTP , Deficiência Intelectual , Criança , Família , Heterozigoto , Humanos , Deficiência Intelectual/genética , Sequenciamento Completo do Exoma
16.
BMC Pediatr ; 21(1): 256, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074259

RESUMO

BACKGROUND: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of chronic encephalopathies characterized by epilepsy with comorbid intellectual disability that are frequently associated with de novo nonsynonymous coding variants in ion channels, cell-surface receptors, and other neuronally expressed genes. Mutations in TRPM3 were identified as the cause of DEE. We report a novel patient with DEE carrying a de novo missense mutation in TRPM3, p.(S1202T); this missense mutation has never been reported. CASE PRESENTATION: A 7-year and 2-month-old Chinese patient who had recurrent polymorphic seizures was clinically diagnosed with DEE. A de novo missense mutation in TRPM3, which has not yet been reported, was identified in this case. The patient had a clinical phenotype consistent with previous reports. CONCLUSIONS: These findings could expand the spectrum of TRPM3 mutations and might also support that de novo substitutions of TRPM3 are a cause of DEE.


Assuntos
Epilepsia , Deficiência Intelectual , Canais de Cátion TRPM , Criança , China , Epilepsia/genética , Humanos , Lactente , Deficiência Intelectual/genética , Mutação , Mutação de Sentido Incorreto , Fenótipo , Canais de Cátion TRPM/genética
17.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070208

RESUMO

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat-Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Hirschsprung/imunologia , Deficiência Intelectual/imunologia , Microcefalia/imunologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/imunologia , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Facies , Feminino , Perfilação da Expressão Gênica , Haploinsuficiência , Doença de Hirschsprung/genética , Humanos , Imunidade Celular , Memória Imunológica/genética , Deficiência Intelectual/genética , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Knockout , Microcefalia/genética , Mutação , Subpopulações de Linfócitos T/imunologia , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de Zinco/deficiência , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
18.
Am J Hum Genet ; 108(7): 1342-1349, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34143952

RESUMO

EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Defeitos Congênitos da Glicosilação/genética , Retículo Endoplasmático/genética , alfa-Manosidase/genética , Adolescente , Alelos , Proteínas de Ligação ao Cálcio/deficiência , Linhagem Celular , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/sangue , Deficiências do Desenvolvimento/genética , Feminino , Glicoproteínas/sangue , Glicosilação , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Mutação , Linhagem , Polissacarídeos/sangue , Deficiências na Proteostase/genética , alfa-Manosidase/deficiência
19.
Medicine (Baltimore) ; 100(23): e26093, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114993

RESUMO

RATIONALE: Mutations of connector enhancer of kinase suppressor of Ras-2 (CNKSR2) gene were identified as the cause of Houge type of X-linked syndromic mental retardation. The mutations of CNKSR2 gene are rare, we reporta patient carrying a novel nonsense mutation of CNKSR2,c.625C > T(p.Gln209∗) and review the clinical features and mutations of CNKSR2 gene for this rare condition considering previous literature. PATIENT CONCERNS: We report a case of a 7-year and 5-month-old Chinese patient with clinical symptoms of intellectual disability, language defect, epilepsy and hyperactivity. Genetic study revealed a novel nonsense variant of CNKSR2, which has not been reported yet. DIAGNOSIS: According to clinical manifestations, genetic pattern and ACMG classification of mutation site as Class 1-cause disease, the patient was diagnosed as Houge type of X-linked syndromic mental retardation caused by CNKSR2 gene mutation. INTERVENTIONS: The patient was administrated with a gradual titration of valproic acid (VPA). OUTCOMES: On administration of valproic acid, he had no further seizures. LESSONS: This is the first time to report a nonsense variant in CNKSR2, c.625C > T(p.Gln209∗), this finding could expand the spectrum of CNKSR2 mutations and might also support the further study of Houge type of X-linked syndromic mental retardation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Epilepsia , Deficiência Intelectual , Transtornos da Linguagem , Retardo Mental Ligado ao Cromossomo X , Agitação Psicomotora , Ácido Valproico/administração & dosagem , Anticonvulsivantes/administração & dosagem , Criança , Códon sem Sentido , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/prevenção & controle , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos da Linguagem/diagnóstico , Transtornos da Linguagem/genética , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/tratamento farmacológico , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Agitação Psicomotora/diagnóstico , Agitação Psicomotora/etiologia , Avaliação de Sintomas , Resultado do Tratamento
20.
Commun Biol ; 4(1): 666, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079053

RESUMO

Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.


Assuntos
Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Trocador de Sódio e Cálcio/genética , Trocador de Sódio e Cálcio/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sinalização do Cálcio , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/química , Proteínas Mitocondriais/deficiência , Plasticidade Neuronal , Neurônios/metabolismo , Linhagem , Mutação Puntual , Terminações Pré-Sinápticas/metabolismo , Trocador de Sódio e Cálcio/química , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
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