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1.
Proc Natl Acad Sci U S A ; 118(3)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33408250

RESUMO

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

2.
Sci Rep ; 10(1): 19030, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33149206

RESUMO

Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson-Forssman-Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females. To investigate the mechanisms behind overlapping but distinct clinical aspects between genders, we assessed the consequences of individual variants with structural modelling and molecular techniques. We found evidence that de novo variants occurring in females are more severe and result in loss of PHF6, while inherited variants identified in males might be hypomorph or have weaker effects on protein stability. This might contribute to the different phenotypes in male versus female individuals with BFLS. Furthermore, we used CRISPR/Cas9 to induce knockout of PHF6 in SK-N-BE (2) cells which were then differentiated to neuron-like cells in order to model nervous system related consequences of PHF6 loss. Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development. Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration. Impairment of these processes might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.

3.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
4.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
5.
Sci Rep ; 10(1): 1204, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988313

RESUMO

Neurodevelopmental disorders (NDDs) are clinically and genetically extremely heterogeneous with shared phenotypes often associated with genes from the same networks. Mutations in TCF4, MEF2C, UBE3A, ZEB2 or ATRX cause phenotypically overlapping, syndromic forms of NDDs with severe intellectual disability, epilepsy and microcephaly. To characterize potential functional links between these genes/proteins, we screened for genetic interactions in Drosophila melanogaster. We induced ubiquitous or tissue specific knockdown or overexpression of each single orthologous gene (Da, Mef2, Ube3a, Zfh1, XNP) and in pairwise combinations. Subsequently, we assessed parameters such as lethality, wing and eye morphology, neuromuscular junction morphology, bang sensitivity and climbing behaviour in comparison between single and pairwise dosage manipulations. We found most stringent evidence for genetic interaction between Ube3a and Mef2 as simultaneous dosage manipulation in different tissues including glia, wing and eye resulted in multiple phenotype modifications. We subsequently found evidence for physical interaction between UBE3A and MEF2C also in human cells. Systematic pairwise assessment of the Drosophila orthologues of five genes implicated in clinically overlapping, severe NDDs and subsequent confirmation in a human cell line revealed interactions between UBE3A/Ube3a and MEF2C/Mef2, thus contributing to the characterization of the underlying molecular commonalities.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epistasia Genética/genética , Fatores de Regulação Miogênica/genética , Transtornos do Neurodesenvolvimento/genética , Ubiquitina-Proteína Ligases/genética , Animais , Modelos Animais de Doenças , Olho/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Fatores de Transcrição MEF2/genética , Neuroglia/metabolismo , Fenótipo , RNA Interferente Pequeno , Transfecção , Asas de Animais/metabolismo
6.
Neuron ; 101(6): 1089-1098.e4, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30713029

RESUMO

Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. VIDEO ABSTRACT.


Assuntos
Apoptose , Citocinese , Mitose , Células-Tronco Neurais/metabolismo , Septinas/metabolismo , Proteínas não Estruturais Virais/metabolismo , Zika virus/metabolismo , Citoesqueleto/metabolismo , Células HEK293 , Células HeLa , Humanos , Neurogênese , RNA Helicases/metabolismo , Serina Endopeptidases/metabolismo
7.
Ann Neurol ; 84(5): 638-647, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30178464

RESUMO

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.


Assuntos
Tronco Encefálico/anormalidades , Caderinas/genética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação
8.
Am J Hum Genet ; 103(2): 305-316, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057029

RESUMO

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.


Assuntos
Proteínas F-Box/genética , Variação Genética/genética , Transtornos do Neurodesenvolvimento/genética , Proteína-Arginina N-Metiltransferases/genética , Criança , Exoma/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Complexo de Endopeptidases do Proteassoma/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Sequenciamento Completo do Exoma/métodos
9.
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
10.
Am J Hum Genet ; 101(3): 441-450, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28823706

RESUMO

Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.


Assuntos
Doenças Cerebelares/genética , Proteínas Ativadoras de GTPase/genética , Homozigoto , Microcefalia/genética , Mutação , Adolescente , Animais , Doenças Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Células HeLa , Humanos , Masculino , Microcefalia/patologia , Linhagem , Fenótipo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
11.
Nat Genet ; 49(3): 457-464, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28092684

RESUMO

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.


Assuntos
Doenças Cerebelares/genética , Exonucleases/genética , Mutação/genética , Proteínas Nucleares/genética , RNA Nuclear Pequeno/genética , Alelos , Animais , Feminino , Humanos , Masculino , Camundongos , Doenças Neurodegenerativas/genética , RNA Mensageiro/genética , Spliceossomos/genética , Peixe-Zebra
12.
Am J Med Genet A ; 170(3): 670-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26842493

RESUMO

We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Mutação Puntual , Convulsões/genética , Proteínas de Transporte Vesicular/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Facies , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/tratamento farmacológico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Expressão Gênica , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/tratamento farmacológico , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/patologia , Índice de Gravidade de Doença , Síndrome , Adulto Jovem
13.
Am J Med Genet A ; 167A(11): 2503-2507, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26109232

RESUMO

We report on two families, each with documented consanguinity and two affected with overlapping features of Dandy-Walker malformation, genitourinary abnormalities, intellectual disability, and hearing deficit. This phenotype shares similar findings with many well-known syndromes. However, the clinical findings of this syndrome categorize this as a new syndrome as compared with the phenotype of already established syndromes. Due to parental consanguinity, occurrence in siblings of both genders and the absence of manifestations in obligate carrier parents, an autosomal recessive pattern of inheritance is more likely. The authors believe that these families suggest a novel autosomal recessive cerebello-genital syndrome. Array CGH analyses of an affected did not show pathological deletions or duplications.


Assuntos
Síndrome de Dandy-Walker/complicações , Deficiência Intelectual/complicações , Anormalidades Urogenitais/complicações , Pré-Escolar , Família , Feminino , Humanos , Lactente , Masculino , Linhagem
14.
Hum Mutat ; 35(12): 1495-505, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25224183

RESUMO

Glycoprotein M6A (GPM6A) is a neuronal transmembrane protein of the PLP/DM20 (proteolipid protein) family that associates with cholesterol-rich lipid rafts and promotes filopodia formation. We identified a de novo duplication of the GPM6A gene in a patient with learning disability and behavioral anomalies. Expression analysis in blood lymphocytes showed increased GPM6A levels. An increase of patient-derived lymphoblastoid cells carrying membrane protrusions supports a functional effect of this duplication. To study the consequences of GPM6A dosage alterations in an intact nervous system, we employed Drosophila melanogaster as a model organism. We found that knockdown of Drosophila M6, the sole member of the PLP family in flies, in the wing, and whole organism causes malformation and lethality, respectively. These phenotypes as well as the protrusions of patient-derived lymphoblastoid cells with increased GPM6A levels can be alleviated by cholesterol supplementation. Notably, overexpression as well as loss of M6 in neurons specifically compromises long-term memory in the courtship conditioning paradigm. Our findings thus indicate a critical role of correct GPM6A/M6 levels for cognitive function and support a role of the GPM6A duplication for the patient's phenotype. Together with other recent findings, this study highlights compromised cholesterol homeostasis as a recurrent feature in cognitive phenotypes.


Assuntos
Colesterol/fisiologia , Transtornos Cognitivos/genética , Dosagem de Genes , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Duplicação Gênica , Humanos , Hibridização in Situ Fluorescente , Locomoção , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Comportamento Sexual Animal
15.
Am J Hum Genet ; 93(1): 124-31, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23746550

RESUMO

An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation. Furthermore, an individual with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three individuals with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.


Assuntos
Mutação da Fase de Leitura , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Adolescente , Fator de Ligação a CCCTC , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , Análise Mutacional de DNA , Elementos Facilitadores Genéticos , Exoma , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano , Haploinsuficiência , Humanos , Masculino , Microcefalia/genética , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Transdução de Sinais
16.
Am J Med Genet A ; 158A(7): 1765-70, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22678764

RESUMO

We report on a 16-year-old male patient with moderate intellectual disability, behavioral problems, and further anomalies such as facial dysmorphism, heart defect, and urogenital anomalies. By molecular karyotyping we identified the first de novo copy number gain to four copies on chromosome 17q21.31 including the MAPT gene but not the entire recurrent microdeletion/microduplication region. Recurrent microdeletions of this region including the MAPT and the CHRH1 genes have been shown to be a relatively frequent cause of intellectual disability, while only a few reciprocal duplications in patients with variable cognitive disorders have been published so far. A common inversion polymorphism in this region has been linked to a distinct H2 haplotype and seems to be associated with an increased risk for microdeletions and -duplications. Our patient and his father were both heterozygous for the H1/H2 haplotype, whereas the mother was homozygous for the H2 haplotype. In our patient the dosage gain apparently occurred on the paternal H1 allele and did not involve the H2 allele as in the previously published cases. This patient further delineates the genotypic and phenotypic variability associated with copy number variants from the 17q21.31 microdeletion region.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 17 , Dosagem de Genes , Deficiência Intelectual/genética , Proteínas tau/genética , Adolescente , Alelos , Heterozigoto , Humanos , Cariotipagem , Masculino , Linhagem
17.
BMC Med Genet ; 12: 106, 2011 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-21827697

RESUMO

BACKGROUND: Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. METHODS: 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. RESULTS: By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. CONCLUSIONS: We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Alelos , Proteínas de Ligação ao Cálcio , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Códon de Terminação , Facies , Feminino , Mutação da Fase de Leitura , Deleção de Genes , Heterozigoto , Humanos , Hiperventilação/genética , Cariotipagem , Masculino , Moléculas de Adesão de Célula Nervosa , Sítios de Splice de RNA , Adulto Jovem
18.
Hum Mutat ; 31(6): 722-33, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20513142

RESUMO

The etiology of mental retardation remains elusive in the majority of cases. Microdeletions within chromosomal bands 5q14.3q15 were recently identified as a recurrent cause of severe mental retardation, epilepsy, muscular hypotonia, and variable minor anomalies. By molecular karyotyping we identified two novel 2.4- and 1.5-Mb microdeletions of this region in patients with a similar phenotype. Both deletions contained the MEF2C gene, which is located proximally to the previously defined smallest region of overlap. Nevertheless, due to its known role in neurogenesis, we considered MEF2C as a phenocritical candidate gene for the 5q14.3q15 microdeletion phenotype. We therefore performed mutational analysis in 362 patients with severe mental retardation and found two truncating and two missense de novo mutations in MEF2C, establishing defects in this transcription factor as a novel relatively frequent autosomal dominant cause of severe mental retardation accounting for as much as 1.1% of patients. In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. We therefore conclude that the phenotypic overlap of patients with MEF2C mutations and atypical Rett syndrome is due to the involvement of a common pathway.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Deficiência Intelectual/genética , Proteínas de Domínio MADS/genética , Mutação de Sentido Incorreto , Fatores de Regulação Miogênica/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , DNA/química , DNA/metabolismo , Análise Mutacional de DNA , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Humanos , Deficiência Intelectual/patologia , Cariotipagem , Luciferases/genética , Luciferases/metabolismo , Proteínas de Domínio MADS/química , Proteínas de Domínio MADS/metabolismo , Fatores de Transcrição MEF2 , Masculino , Modelos Moleculares , Fatores de Regulação Miogênica/química , Fatores de Regulação Miogênica/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Síndrome
19.
Clin Cancer Res ; 9(7): 2472-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12855620

RESUMO

PURPOSE: Our goal was to find the maximum tolerated dose of gemcitabine administered concurrently with thoracic radiotherapy in locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III NSCLC and a radiation planning volume less than 2000 cm(3) were included. Treatment consisted of 6 weeks of thoracic radiation, 2 Gy daily for 5 days a week for a total dose of 60 Gy. Planning with multiple field arrangements and three-dimensional conformal technique was used. Patients were treated with gemcitabine, starting with a dose of 300 mg/m(2) in the 1st week of radiation. In subsequent cohorts, the weekly dosing frequency of gemcitabine was increased until weekly administration was reached. Thereafter, the doses of weekly gemcitabine were increased. Toxicity was measured using Common Toxicity of the National Cancer Institute (CTC), acute Radiation Therapy Oncology Group (RTOG), and late RTOG/European Organization for Research and Treatment of Cancer (EORTC) rating scales. RESULTS: Twenty-seven patients were included, of whom 14 had stage IIIa and 13 had stage IIIb. Dose-limiting toxicity was grade 3 esophagitis and grade 3 radiation pneumonitis in the patient cohort receiving gemcitabine 450 mg/m(2) once weekly. The mean actual treated radiation volume was 760 cm(3) (range, 289-1718 cm(3)). CONCLUSIONS: The maximum tolerated dose and frequency of gemcitabine in locally advanced NSCLC is 300 mg/m(2) once weekly during 6 weeks of thoracic radiotherapy, as long as the treatment volume does not exceed 2000 cm(3).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Adulto , Idoso , Estudos de Coortes , Terapia Combinada , Relação Dose-Resposta a Droga , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
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