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1.
Am J Hum Genet ; 105(3): 493-508, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447100

RESUMO

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

2.
J Mol Neurosci ; 64(2): 331, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29353437

RESUMO

The original version of this article unfortunately contained mistakes.

4.
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
5.
Eur J Hum Genet ; 24(5): 652-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26306646

RESUMO

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/diagnóstico , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade
6.
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.

7.
Eur J Med Genet ; 58(10): 503-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26327614

RESUMO

Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.


Assuntos
Cromossomos Humanos Par 1/genética , Anormalidades Craniofaciais/genética , Megalencefalia/genética , Sobrepeso/genética , Trissomia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Lactente , Masculino , Megalencefalia/diagnóstico , Sobrepeso/diagnóstico , Síndrome , Gêmeos Monozigóticos/genética
8.
PLoS One ; 10(7): e0131486, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26222316

RESUMO

Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS), a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET) and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.


Assuntos
Encéfalo , Flumazenil/administração & dosagem , Síndrome do Cromossomo X Frágil , Tomografia por Emissão de Pósitrons , Receptores de GABA-A/metabolismo , Adolescente , Adulto , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Radiografia
9.
BMC Med Genet ; 16: 51, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-26189493

RESUMO

BACKGROUND: Identification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum. METHODS: Whole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed. RESULTS: A de novo KCND3 mutation (c.877_885dupCGCGTCTTC; p.Arg293_Phe295dup) was found duplicating the RVF motif and thereby adding an extra positive charge to voltage-gated potassium 4.3 (Kv4.3) in the voltage-sensor domain causing a severe shift of the voltage-dependence gating to more depolarized voltages. The patient displayed a severe phenotype with early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. CONCLUSIONS: We identified a de novo KCND3 mutation causing the most marked change in Kv4.3's channel properties reported so far, which correlated with a severe and unique spinocerebellar ataxia (SCA) type 19/22 disease phenotype.


Assuntos
Apraxias/genética , Deficiência Intelectual/genética , Canais de Potássio Shal/genética , Degenerações Espinocerebelares/genética , Sequência de Bases , Linhagem Celular Tumoral , Criança , Epilepsia/genética , Marcadores Genéticos , Células HeLa , Humanos , Masculino , Técnicas de Patch-Clamp , Análise de Sequência de DNA
11.
Hum Mutat ; 36(6): 593-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25824905

RESUMO

Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis.


Assuntos
Encéfalo/anormalidades , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Anormalidades do Olho/genética , Genes Recessivos , Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Mutação , Dermatoses do Couro Cabeludo/congênito , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genética , Tomografia Computadorizada por Raios X , Adulto Jovem
12.
Eur J Hum Genet ; 23(6): 803-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25205402

RESUMO

AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3' transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder.


Assuntos
Deleção de Genes , Deficiência Intelectual/genética , Microcefalia/genética , Polimorfismo Genético , Proteínas/genética , Éxons , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome , Adulto Jovem
13.
Am J Med Genet A ; 164A(12): 3061-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25256099

RESUMO

Small interstitial deletions affecting chromosome region 3p25.3 have been reported in only five patients so far, four of them with overlapping telomeric microdeletions 3p25.3 and variable features of 3p- syndrome, and one patient with a small proximal microdeletion and a distinct phenotype with intellectual disability (ID) and multiple congenital anomalies. Here we report on three novel patients with overlapping proximal microdeletions 3p25.3 of 1.1-1.5 Mb in size showing a consistent non-3p- phenotype with ID, epilepsy/EEG abnormalities, poor speech, ataxia and stereotypic hand movements. The smallest region of overlap contains two genes encoding sodium- and chloride-dependent GABA transporters which have not been associated with this disease phenotype in humans so far. The protein function, the phenotype in transporter deficient animal models and the effects of specific pharmacological transporter inhibition in mice and humans provide evidence that these GABA transporters are plausible candidates for seizures/EEG abnormalities, ataxia and ID in this novel group of patients. A fourth novel patient deleted for a 3.16 Mb region, both telomeric and centromeric to 3p25.3, confirms that the telomeric segment is critical for the 3p- syndrome phenotype. Finally, a region of 643 kb is suggested to harbor one or more genes causative for polydactyly which is part of the 3p- syndrome.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Epilepsia/genética , Proteínas da Membrana Plasmática de Transporte de GABA/deficiência , Deficiência Intelectual/genética , Anormalidades Múltiplas/patologia , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Comportamento Estereotipado
14.
Am J Med Genet C Semin Med Genet ; 166C(3): 315-26, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25169753

RESUMO

Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.


Assuntos
Transtorno Autístico/genética , Proteínas de Homeodomínio/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/genética , Animais , Transtorno Autístico/etiologia , Pré-Escolar , DNA Helicases/genética , DNA Helicases/metabolismo , Face/anormalidades , Deformidades Congênitas da Mão/genética , Haploinsuficiência/genética , Humanos , Lactente , Deficiência Intelectual/genética , Camundongos Knockout , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligopeptídeos/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Eur J Med Genet ; 57(4): 151-6, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24534801

RESUMO

After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis.


Assuntos
Hibridização Genômica Comparativa/métodos , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Diagnóstico Pré-Natal/métodos , Bélgica , Consenso , Feminino , Humanos , Guias de Prática Clínica como Assunto , Gravidez
17.
Nat Genet ; 46(4): 380-4, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24531329

RESUMO

Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Sequência de Bases , Códon sem Sentido/genética , Exoma/genética , Mutação da Fase de Leitura/genética , Componentes do Gene , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA
18.
Eur J Hum Genet ; 22(11): 1272-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24424121

RESUMO

Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.


Assuntos
Criptorquidismo/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Hipertrofia/genética , Deficiência Intelectual/genética , Artropatias/genética , Proteína Smad4/genética , Adolescente , Adulto , Criança , Facies , Feminino , Seguimentos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA , Adulto Jovem
19.
Eur J Hum Genet ; 22(5): 652-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24105367

RESUMO

Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Bandeamento Cromossômico , Duplicação Cromossômica , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 21 , Hibridização Genômica Comparativa , Biologia Computacional , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Cariótipo , Masculino , Recombinação Genética
20.
Eur J Hum Genet ; 21(12): 1349-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23632790

RESUMO

The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.


Assuntos
Plaquetas/metabolismo , Cromossomos Humanos Par 14/genética , Fatores de Transcrição Forkhead/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Síndrome de Rett/genética , Translocação Genética/genética , Adulto , Encéfalo/metabolismo , Criança , Feminino , Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Proteínas do Tecido Nervoso/metabolismo , Síndrome de Rett/metabolismo , Pele/metabolismo
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