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1.
Cytogenet Genome Res ; 159(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658463

RESUMO

The switch/sucrose non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeller that regulates the spacing of nucleosomes and thereby controls gene expression. Heterozygous mutations in genes encoding subunits of the SWI/SNF complex have been reported in individuals with Coffin-Siris syndrome (CSS), with the majority of the mutations in ARID1B. CSS is a rare congenital disorder characterized by facial dysmorphisms, digital anomalies, and variable intellectual disability. We hypothesized that mutations in genes encoding subunits of the ubiquitously expressed SWI/SNF complex may lead to alterations of the nucleosome profiles in different cell types. We performed the first study on CSS-patient samples and investigated the nucleosome landscapes of cell-free DNA (cfDNA) isolated from blood plasma by whole-genome sequencing. In addition, we studied the nucleosome landscapes of CD14+ monocytes from CSS-affected individuals by nucleosome occupancy and methylome-sequencing (NOMe-seq) as well as their expression profiles. In cfDNA of CSS-affected individuals with heterozygous ARID1B mutations, we did not observe major changes in the nucleosome profile around transcription start sites. In CD14+ monocytes, we found few genomic regions with different nucleosome occupancy when compared to controls. RNA-seq analysis of CD14+ monocytes of these individuals detected only few differentially expressed genes, which were not in proximity to any of the identified differential nucleosome-depleted regions. In conclusion, we show that heterozygous mutations in the human SWI/SNF subunit ARID1B do not have a major impact on the nucleosome landscape or gene expression in blood cells. This might be due to functional redundancy, cell-type specificity, or alternative functions of ARID1B.

2.
Am J Hum Genet ; 104(6): 1223-1232, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130282

RESUMO

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

3.
Hum Genet ; 137(9): 753-768, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167850

RESUMO

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.


Assuntos
Proteínas de Transporte/genética , Canalopatias/genética , Deficiências do Desenvolvimento/genética , Marcadores Genéticos , Variação Genética , Proteínas de Membrana/genética , Canais de Sódio/genética , Adolescente , Adulto , Canalopatias/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
4.
Brain ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985992

RESUMO

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

5.
Cytogenet Genome Res ; 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30016768

RESUMO

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deletion of the maternally inherited 15q11q13 region, paternal uniparental disomy 15 [upd(15)pat], an imprinting defect of the maternal chromosome region 15q11q13, or a pathogenic mutation of the maternal UBE3A allele. Predisposing factors for upd(15)pat, such as nonhomologous robertsonian translocation involving chromosome 15, have been discussed, but no evidence for this predisposition has been published. In the present study, chromosomal analysis was performed in a child with AS, both parents, and the maternal grandparents. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was employed on DNA of the index individual, and microsatellite analysis was carried out on DNA of the index individual and his parents. The cytogenetic analysis showed that the mother and maternal grandfather are carriers of a rob(14;15). The index individual has a numerically normal karyotype, but MS-MLPA and microsatellite analyses confirmed the clinical diagnosis of AS and revealed a pattern highly suggestive of isodisomic upd(15)pat. This is the first report of an AS-affected individual with isodisomic upd(15)pat and a numerically normal karyotype that most likely results from a rob(14;15)-associated meiotic error in the maternal germline followed by monosomy 15 rescue in the early embryo.

6.
Hum Mutat ; 39(9): 1246-1261, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29924900

RESUMO

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

7.
Am J Hum Genet ; 102(3): 468-479, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429572

RESUMO

Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

8.
Hum Genet ; 136(7): 821-834, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28393272

RESUMO

Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.


Assuntos
Epilepsia/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Heterozigoto , Deficiência Intelectual/genética , Idade de Início , Agenesia do Corpo Caloso/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1 , Epilepsia/diagnóstico , Feminino , Variação Genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Rim/anormalidades , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Fenótipo , Processamento de RNA , Ribonucleoproteínas Nucleares Pequenas/genética , Convulsões/diagnóstico , Convulsões/genética
9.
Hum Genet ; 136(3): 307-320, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28120103

RESUMO

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.


Assuntos
Cromatina/fisiologia , Síndrome de Lange/genética , Mutação , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Facies , Feminino , Humanos , Masculino , Adulto Jovem
10.
Hum Genet ; 136(3): 297-305, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28124119

RESUMO

Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin-Siris (CSS) and Nicolaides-Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Heterozigoto , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fenótipo , Fatores de Transcrição/genética , Humanos , Lactente , Masculino
11.
Hum Genet ; 136(2): 179-192, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27848077

RESUMO

The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.


Assuntos
Transtorno Autístico/genética , Proteínas de Transporte/genética , Variação Genética , Deficiência Intelectual/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Transtorno Autístico/diagnóstico , Sequência de Bases , Criança , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Deficiência Intelectual/diagnóstico , Cariotipagem , Masculino , Mutação de Sentido Incorreto , Fenótipo , Proteólise , Processamento de RNA , Análise de Sequência de DNA
12.
Epileptic Disord ; 18(2): 123-36, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27267311

RESUMO

KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Epilepsia/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Polegar/anormalidades , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/tratamento farmacológico , Anormalidades Craniofaciais/fisiopatologia , Eletroencefalografia , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Fibromatose Gengival/tratamento farmacológico , Fibromatose Gengival/fisiopatologia , Hallux/fisiopatologia , Deformidades Congênitas da Mão/tratamento farmacológico , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Masculino , Unhas Malformadas/tratamento farmacológico , Unhas Malformadas/fisiopatologia , Síndrome , Polegar/fisiopatologia , Adulto Jovem
14.
Hum Mutat ; 36(11): 1112, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26457590

RESUMO

The original article to which this Erratum refers was published in Human Mutation 36(6):593­598(DOI:10.1002/humu22795).The authors realized that a co-author, Nuria C. Bramswig, was left off of the title page of this article at the time of submission. This erratum serves to correct this error by including Dr. Bramswig and Dr. Bramswig's institution in the title page information.The authors regret the error.

15.
Hum Genet ; 134(10): 1089-97, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26264464

RESUMO

KCNH1 mutations have recently been described in six individuals with Temple-Baraitser syndrome (TMBTS) and six individuals with Zimmermann-Laband syndrome (ZLS). TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis. In this study, we present four additional unrelated individuals with de novo KCNH1 mutations from ID cohorts. We report on a novel recurrent pathogenic KCNH1 variant in three individuals and add a fourth individual with a previously TMBTS-associated KCNH1 variant. Neither TMBTS nor ZLS was suspected clinically. KCNH1 encodes a voltage-gated potassium channel, which is not only highly expressed in the central nervous system, but also seems to play an important role during development. Clinical evaluation of our mutation-positive individuals revealed that one of the main characteristics of TMBTS/ZLS, namely the pronounced nail hypoplasia of the great toes and thumbs, can be mild and develop over time. Clinical comparison of all published KCNH1 mutation-positive individuals revealed a similar facial but variable limb phenotype. KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. In summary, we show that the phenotypic variability of individuals with KCNH1 mutations is more pronounced than previously expected, and we discuss whether KCNH1 mutations allow for "lumping" or for "splitting" of TMBTS and ZLS.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Polegar/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Fibromatose Gengival/patologia , Hallux/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto , Unhas Malformadas/patologia , Polegar/patologia
16.
Hum Genet ; 134(6): 553-68, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25724810

RESUMO

Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann-Steiner, Kabuki, and Adams-Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Exoma , Face/anormalidades , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Hipotricose/diagnóstico , Hipotricose/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Micrognatismo/diagnóstico , Micrognatismo/genética , Mutação , Pescoço/anormalidades , Adulto , Idoso de 80 Anos ou mais , Criança , DNA Helicases/genética , Diagnóstico Diferencial , Facies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Receptores de N-Metil-D-Aspartato/genética , Fatores de Transcrição/genética
17.
Cell Metab ; 19(1): 135-45, 2014 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-24374217

RESUMO

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing ß cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human ß cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased ß cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Proteínas de Membrana/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Sequência de Bases , Cromossomos Humanos Par 14/genética , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica , Impressão Genômica , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
18.
Diabetologia ; 57(3): 451-4, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24362728

RESUMO

Gene regulation in human pancreatic endocrine cells is a complex process, governed by genetic and environmental factors and crosstalk between the various endocrine cell types, and between endocrine cells and the metabolic state. Recent advances in gene expression profiling, genome-wide analysis of epigenetic marks, and cell fractionation of human islets into their constitutive cell types have greatly increased our understanding of the complex processes that govern endocrine cell function in health and disease. Further progress in this area holds great promise for delivering new targets for the development of novel diabetes therapies.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética , Histonas/metabolismo , Ilhotas Pancreáticas/metabolismo , Transcrição Genética , Diabetes Mellitus Tipo 2/genética , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Estilo de Vida , Ativação Transcricional
19.
J Clin Invest ; 123(3): 1275-84, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23434589

RESUMO

Insulin-secreting ß cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, ß, and exocrine cells. We found that, compared with exocrine and ß cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for ß cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in ß cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to ß cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type-specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.


Assuntos
Epigênese Genética , Células Secretoras de Glucagon/fisiologia , Células Secretoras de Insulina/fisiologia , Processamento de Proteína Pós-Traducional , Animais , Diferenciação Celular , Separação Celular , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Células Secretoras de Glucagon/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Metilação , Camundongos , Anotação de Sequência Molecular , Análise de Sequência de RNA , Transcriptoma
20.
Trends Endocrinol Metab ; 23(6): 286-91, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22424897

RESUMO

Epigenetic mechanisms may contribute to the pathogenesis of complex diseases. Early or late environmental influences such as intrauterine malnutrition or sedentary lifestyle have been shown to lead to an increased risk of diabetes. Recently, epigenetic mechanisms were shown to be involved in endocrine cell differentiation and islet function. Genomic profiling of pancreatic islets in non-diabetic and diabetic states is needed in order to dissect the contribution of epigenetic mechanisms to the declining proliferation potential of ß cells that we see with aging or the ß-cell failure observed in diabetes. In-depth understanding of epigenetic landscapes can help to improve protocols for in vitro differentiation towards the ß-cell fate, enhance ß-cell proliferation, and lead to the discovery of novel therapeutic targets.


Assuntos
Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Epigenômica/tendências , Envelhecimento/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células , Diabetes Mellitus/fisiopatologia , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Modelos Animais
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