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1.
Front Neurosci ; 13: 42, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30853880

RESUMO

Aggressive behavior is associated with dysfunctional frontolimbic emotion regulation circuits. Recent findings suggest serotonin as a primary transmitter for prefrontal amygdala control. However, the association between serotonin levels, amygdala regulation, and aggression is still a matter of debate. Neurobehavioral models furthermore suggest a possible mediating influence of the monoamine oxidase A gene (MAOA) on this brain-behavior relationship, with carriers of low expressing allele varieties being a risk group for aggression. In the present study, we investigated the influence of brain serotonin modulation and MAOA genotype on functional amygdala connectivity during aggressive behavior. Modulation of serotonergic neurotransmission with acute tryptophan depletion (ATD) and placebo were administered in a double-blind, cross-over design in 38 healthy male participants. Aggressive behavior was modeled in a violent video game during simultaneous assessment of brain activation with functional magnetic resonance imaging (fMRI). Trait aggression was measured with the Buss-Perry Aggression Questionnaire (BP-AQ), and MAOA genotypes were assessed from blood samples. Voxel-wise functional connectivity with anatomically defined amygdala was calculated from the functional data. Tryptophan depletion with ATD reduced aggression-specific amygdala connectivity with bilateral supramarginal gyrus. Moreover, ATD impact was associated with trait aggression and MAOA genotype in prefrontal cortex regions. In summary, serotonergic corticolimbic projections contribute to aggressive behavior. Genotype-specific vulnerability of frontolimbic projections may underlie the elevated risk in low expressing allele carriers.

2.
J Pediatr ; 199: 22-28.e6, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753540

RESUMO

OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.


Assuntos
Rim Policístico Autossômico Recessivo/terapia , Diálise Renal , Medição de Risco , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Rim Policístico Autossômico Recessivo/diagnóstico , Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Ultrassonografia Pré-Natal
3.
J Perinat Med ; 46(2): 169-173, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-28753543

RESUMO

Preeclampsia (PE) affects 2-5% of all pregnancies. It is a multifactorial disease, but it has been estimated that 35% of the variance in liability of PE are attributable to maternal genetic effects and 20% to fetal genetic effects. PE has also been reported in women delivering children with Beckwith-Wiedemann syndrome (BWS, OMIM 130650), a disorder associated with aberrant methylation at genomically imprinted loci. Among others, members of the NLRP gene family are involved in the etiology of imprinting defects. Thus, a functional link between PE, NLRP gene mutations and aberrant imprinting can be assumed. Therefore we analyzed a cohort of 47 PE patients for NLRP gene mutations by next generation sequencing. In 25 fetuses where DNA was available we determined the methylation status at the imprinted locus. With the exception of one woman heterozygous for a missense variant in the NLRP7 gene (NM_001127255.1(NLRP7):c.542G>C) we could not identify further carriers, in the fetal DNA normal methylation patterns were observed. Thus, our negative screening results in a well-defined cohort indicate that NLRP mutations are not a relevant cause of PE, though strong evidence for a functional link between NLRP mutations, PE and aberrant methylation exist.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Metilação de DNA/fisiologia , Impressão Genômica/fisiologia , Pré-Eclâmpsia , Adulto , Feminino , Alemanha/epidemiologia , Humanos , Lactente , Masculino , Mutação , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , Gravidez , Estatística como Assunto
4.
Brain Struct Funct ; 223(2): 873-881, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29019036

RESUMO

Low expressing alleles of the MAOA gene (MAOA-L) have been associated with an increased risk for developing an aggressive personality. This suggests an MAOA-L-specific neurobiological vulnerability associated with trait aggression. The neural networks underlying this vulnerability are unknown. The present study investigated genotype-specific associations between resting state brain networks and trait aggression (Buss-Perry Aggression Questionnaire) in 82 healthy Caucasian males. Genotype influences on aggression-related networks were studied for intrinsic and seed-based brain connectivity. Intrinsic connectivity was higher in the ventromedial prefrontal cortex (VMPFC) of MAOA-L compared to high expressing allele (MAOA-H) carriers. Seed-based connectivity analyses revealed genotype differences in the functional involvement of this region. MAOA genotype modulated the relationship between trait aggression and VMPFC connectivity with supramarginal gyrus (SMG) and areas of the default mode network (DMN). Separate analyses for the two groups were performed to better understand how the genotype modulated the relationship between aggression and brain networks. They revealed a positive correlation between VMPFC connectivity and aggression in right angular gyrus (AG) and a negative correlation in right SMG in the MAOA-L group. No such effect emerged in the MAOA-H carriers. The results indicate a particular relevance of VMPFC for aggression in MAOA-L carriers; in specific, a detachment from the DMN along with a strengthened coupling to the AG seems to go along with lower trait aggression. MAOA-L carriers may thus depend on a synchronization of emotion regulation systems (VMPFC) with core areas of empathy (SMG) to prevent aggression.


Assuntos
Agressão/fisiologia , Encéfalo/fisiologia , Monoaminoxidase/genética , Vias Neurais/fisiologia , Córtex Pré-Frontal/fisiologia , Adolescente , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Frequência do Gene , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Descanso , Inquéritos e Questionários , Adulto Jovem
5.
Pediatr Nephrol ; 32(10): 1989-1992, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28620746

RESUMO

BACKGROUND: Meckel-Gruber syndrome (MKS, OMIM #607361) is a rare pre- or perinatal lethal autosomal recessive ciliopathy caused by mutations in at least 12 known genes. It has a clinical and genetic overlap with other viable ciliopathies, especially Joubert syndrome and Joubert syndrome-related disorders. MKS is characterized by multicystic kidney dysplasia, central nervous system malformations (usually occipital encephalocele), ductal plate malformation of the liver, and postaxial polydactyly. CASE DIAGNOSIS: We identified a homozygous mutation in TMEM67 (MKS3) in a fetus affected by MKS; however, only the mother was a carrier of the respective mutation. Genotyping with polymorphic microsatellite markers and single nucleotide polymorphism (SNP) array revealed a maternal uniparental disomy (UPD) of the entire chromosome 8 (upd(8)mat), harboring TMEM67. CONCLUSIONS: This is the first reported case of UPD as a cause of MKS. The possible underlying mechanisms for uniparental disomy (UPD) are reviewed. Even if rare, awareness of UPD and comprehensive work-up in the case of unexpected homozygosity for a recessive mutation is essential for accurate genetic counseling and assessment of the risk of recurrence.


Assuntos
Cromossomos Humanos Par 8/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Doenças Fetais/genética , Proteínas de Membrana/genética , Doenças Renais Policísticas/genética , Retinite Pigmentosa/genética , Dissomia Uniparental , Aborto Induzido , Adulto , Transtornos da Motilidade Ciliar/diagnóstico , Análise Mutacional de DNA/métodos , Encefalocele/diagnóstico , Feminino , Doenças Fetais/diagnóstico , Testes Genéticos/métodos , Homozigoto , Humanos , Cariotipagem/métodos , Masculino , Mutação , Doenças Renais Policísticas/diagnóstico , Gravidez , Diagnóstico Pré-Natal , Retinite Pigmentosa/diagnóstico , Ultrassonografia Pré-Natal
6.
J Pediatr ; 187: 206-212.e1, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28529015

RESUMO

OBJECTIVE: To investigate the contribution of differential diagnoses to the mutation spectrum of patients referred for Silver-Russell syndrome (SRS) testing. STUDY DESIGN: Forty-seven patients referred for molecular testing for SRS were examined after exclusion of one of the SRS-associated alterations. After clinical classification, a targeted next generation sequencing approach comprising 25 genes associated with other diagnoses or postulated as SRS candidate genes was performed. RESULTS: By applying the Netchine-Harbinson clinical scoring system, indication for molecular testing for SRS was confirmed in 15 out of 47 patients. In 4 out of these 15 patients, disease-causing variants were found in genes associated with other diagnoses. These patients carried mutations associated with Bloom syndrome, Mulibrey nanism, KBG syndrome, or IGF1R-associated short stature. We could not detect any pathogenic mutation in patients with a negative clinical score. CONCLUSIONS: Some of the differential diagnoses detected in the cohort presented here have a major impact on clinical management. Therefore, we emphasize that the molecular defects associated with these clinical pictures should be excluded before the clinical diagnosis "SRS" is made. Finally, we could show that a broad molecular approach including the differential diagnoses of SRS increases the detection rate.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Síndrome de Silver-Russell/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo , Síndrome de Silver-Russell/genética
7.
Nat Genet ; 49(7): 1025-1034, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530676

RESUMO

Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.


Assuntos
Rim Policístico Autossômico Recessivo/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Centríolos/metabolismo , Cromossomos Humanos Par 3/genética , Cílios/metabolismo , Consanguinidade , Modelos Animais de Doenças , Embrião não Mamífero/anormalidades , Feminino , Técnicas de Silenciamento de Genes , Ligação Genética , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Rim Policístico Autossômico Recessivo/embriologia , Transporte Proteico , Septinas/metabolismo , Canais de Cátion TRPP/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia
8.
Pediatr Nephrol ; 32(7): 1269-1273, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28364132

RESUMO

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype-phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation. CASE-DIAGNOSIS/TREATMENT: We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon. CONCLUSIONS: This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD.


Assuntos
Hepatomegalia/genética , Falência Renal Crônica/terapia , Rim/patologia , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Feminino , Testes Genéticos/métodos , Genótipo , Hepatomegalia/diagnóstico por imagem , Humanos , Hiperplasia , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Íntrons/genética , Rim/diagnóstico por imagem , Falência Renal Crônica/etiologia , Imagem por Ressonância Magnética , Mutação , Fenótipo , Mutação Puntual , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/diagnóstico por imagem
9.
Arch Gynecol Obstet ; 295(4): 897-906, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28283827

RESUMO

PURPOSE: To investigate the sonographic and clinical genotype-phenotype correlations in autosomal recessive polycystic kidney disease (ARPKD) and other cystic kidney diseases (CKD) in a large cohort of prenatally detected fetuses with hereditary CKD. METHODS: We retrospectively studied the clinical and diagnostic data of 398 patients referred with prenatal ultrasound findings suggestive of CKD between 1994 and 2010. Cases with confirmed hereditary CKD (n = 130) were analyzed as to their prenatal ultrasound findings, genotype, and possible predictors of clinical outcome. RESULTS: ARPKD was most common in our non-representative sample. Truncating PKHD1 mutations led to a significantly reduced neonatal prognosis, with two such mutations being invariably lethal. Sonographically visible kidney cysts occurred in only 3% of ARPKD cases. Renal abnormalities in Meckel syndrome (MKS) appeared earlier than in ADPKD (19.6 ± 3.7 vs. 29.8 ± 5.1 GW) or ARPKD (19.6 ± 3.7 vs. 30.2 ± 1.2 GW). Additional CNS malformations were not found in ARPKD, but were highly sensitive for MKS. Pulmonary hypoplasia, oligo/anhydramnios (OAH), and kidney enlargement were associated with a significantly worse neonatal prognosis. CONCLUSION: Genotype, sonographic signs of OAH, enlarged kidney size, and pulmonary hypoplasia can be useful predictors of neonatal survival. We propose sonographic morphological criteria for ARPKD, ADPKD, MKS, and renal cyst and diabetes syndrome (RCAD). We further propose a clinical diagnostic algorithm for differentiating cystic kidney diseases.


Assuntos
Estudos de Associação Genética , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Transtornos da Motilidade Ciliar/diagnóstico por imagem , Diagnóstico Diferencial , Encefalocele/diagnóstico por imagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Rim/anormalidades , Rim/diagnóstico por imagem , Masculino , Mutação , Doenças Renais Policísticas/diagnóstico por imagem , Rim Policístico Autossômico Recessivo/embriologia , Rim Policístico Autossômico Recessivo/genética , Prognóstico , Receptores de Superfície Celular/genética , Retinite Pigmentosa , Estudos Retrospectivos , Ultrassonografia
10.
Hum Brain Mapp ; 38(3): 1622-1635, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27935229

RESUMO

INTRODUCTION: A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. METHODS: Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. RESULTS: Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. CONCLUSION: MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Córtex Cerebral/patologia , Sistema Límbico/patologia , Monoaminoxidase/genética , Transtornos do Humor , Triptofano/deficiência , Adulto , Córtex Cerebral/diagnóstico por imagem , Estudos Cross-Over , Método Duplo-Cego , Lateralidade Funcional/genética , Interação Gene-Ambiente , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Sistema Límbico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Transtornos do Humor/etiologia , Transtornos do Humor/genética , Transtornos do Humor/patologia , Vias Neurais , Oxigênio/sangue , Adulto Jovem
11.
Brain ; 139(11): 2877-2890, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27543974

RESUMO

Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.


Assuntos
Doenças Cerebelares/genética , Predisposição Genética para Doença/genética , Proteínas Mitocondriais/genética , Mutação/genética , Proteínas de Transporte de Fosfato/genética , Polimorfismo de Nucleotídeo Único/genética , Aminoácidos/genética , Animais , Animais Geneticamente Modificados , Encéfalo/anormalidades , Linhagem Celular Transformada , Células Cultivadas , Doenças Cerebelares/diagnóstico por imagem , Estudos de Coortes , Embrião não Mamífero , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial/genética , Modelos Moleculares , Peixe-Zebra
12.
Gynecol Obstet Invest ; 81(5): 472-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27300293

RESUMO

BACKGROUND: There are only few reports of pregnancy and delivery in non-dystrophic myotonia or periodic paralysis caused by CLCN1 or SCN4A gene mutations. METHODS: We report the medical histories and personal attitudes of 5 unrelated German patients, 2 following autosomal recessive inheritance (case 1; most likely and case 2; confirmed Becker disease) and 3 following autosomal dominant inheritance (case 3; CLCN1 mutation, cases 4-5; SCN4A mutations), who delivered a total of 9 children. RESULTS: Apart from case 5 with periodic paralysis, who had 5 early miscarriages and pre-eclampsia resulting in cesarean delivery, there was no evidence of increased obstetric complication rates, and neonatal outcome was favorable. In all patients, there was aggravation of myotonia or weakness in pregnancy, followed by a short-term improvement after delivery in cases 2 and 3. Mexiletine medication improved the clinical features significantly in case 2 but was unable to control pregnancy-related deterioration. In case 4 (and her sister) and case 5, there was a clear disease aggravation in pregnancy resulting in hospitalization or repeated neurological examinations. CONCLUSION: Pregnancy can be regarded as a strong triggering factor in inherited non-dystrophic myotonias and periodic paralysis, regardless of the underlying gene defect.


Assuntos
Miotonia/genética , Transtornos Miotônicos/genética , Paralisias Periódicas Familiares/genética , Gravidez/fisiologia , Adulto , Canais de Cloreto/genética , Feminino , Humanos , Miotonia/fisiopatologia , Transtornos Miotônicos/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Paralisias Periódicas Familiares/fisiopatologia , Adulto Jovem
13.
Muscle Nerve ; 54(3): 496-500, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26998597

RESUMO

INTRODUCTION: Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). METHODS: We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. RESULTS: We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy. CONCLUSION: These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496-500, 2016.


Assuntos
Genes Dominantes/genética , Extremidade Inferior/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Mutação/genética , Idoso , Análise Mutacional de DNA , Saúde da Família , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
14.
Am J Hum Genet ; 98(3): 473-489, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26924529

RESUMO

Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system.


Assuntos
Fraturas Ósseas/genética , Regulação da Expressão Gênica no Desenvolvimento , Atrofia Muscular Espinal/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Artrogripose/diagnóstico , Artrogripose/genética , Proteínas de Transporte/genética , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Fraturas Ósseas/diagnóstico , Perfilação da Expressão Gênica , Homozigoto , Humanos , Proteínas com Domínio LIM/genética , Camundongos , Dados de Sequência Molecular , Atrofia Muscular Espinal/diagnóstico , Mutação , Proteínas Nucleares/genética , Linhagem , Fenótipo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
15.
Neuromuscul Disord ; 26(2): 132-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26794302

RESUMO

Two Croatian siblings with atypical clinical findings in the presence of SMN1 gene mutations are reported. The girl presented with delayed motor development and weakness in hands and feet in her first year of life. She never stood or walked and developed scoliosis and joint contractures during childhood. Her hands and feet were non-functional when last seen at age 14 years. Her 4-year-old brother was more severely affected and had a clinical picture resembling infantile spinal muscular atrophy (SMA) type 1. He also showed unusual distally pronounced weakness and facial weakness. Both patients had no sensory deficits but gave evidence of a mixed axonal and demyelinating neuropathy with pronounced slowing in the distal nerve segments. Unexpectedly, both siblings showed a compound heterozygous SMN1 mutation (heterozygous deletion and missense mutation c.689C > T; p.S230L), thus confirming infantile SMA. In addition, next generation sequencing of 52 genes for hereditary neuropathies revealed a heterozygous missense mutation c.505T > C; p.Y169H in the SH3TC2 gene that was transmitted by the healthy father. Our observations widen the phenotypic consequences of SMN1 gene mutations and support the notion to look for additional genetic factors which may modify the clinical picture in atypical cases.


Assuntos
Doenças Desmielinizantes/genética , Doenças Desmielinizantes/fisiopatologia , Proteínas/genética , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/fisiopatologia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Masculino , Mutação
16.
Neuroimage ; 125: 378-385, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26481676

RESUMO

A recent [(18)F]FDOPA-PET study reports negative correlations between dopamine synthesis rates and aggressive behavior. Since dopamine is among the substrates for monoamine oxidase A (MAOA), this investigation examines whether functional allelic variants of the MAOA tandem repeat (VNTR) promotor polymorphism, which is known to modulate aggressive behavior, influences dopamine release and aggression in response to violent visual stimuli. We selected from a genetic prescreening sample, strictly case-matched groups of 2×12 healthy male subjects with VNTRs predictive of high (MAOA-High) and low (MAOA-Low) MAOA expression. Subjects underwent pairs of PET sessions (dopamine D2/3 ligand [(18)F]DMFP) while viewing a movie of neutral content, versus violent content. Directly afterwards, aggressive behavior was assessed by the Point Subtraction Aggression Paradigm (PSAP). Finally, PET data of 23 participants and behavioral data of 22 participants were analyzed due to post hoc exclusion criteria. In the genetic prescreening sample MAOA-Low carriers had significantly increased scores on the Buss-Perry Aggression Questionnaire. In the PET-study-group, aggressive behavior under the emotional neutral condition was significantly higher in the MAOA-Low group. Interestingly, the two MAOA-groups showed inverse dopaminergic and behavioral reactions to the violent movie: The MAOA-High group showed higher dopamine release and increased aggression after the violent movie; MAOA-Low subjects showed decreases in aggressive behavior and no consistent dopamine release. These results indicate a possible impact of the MAOA-promotor polymorphism on the neurobiological modulation of aggressive behavior. However, the data do not support approaches stating that MAOA-Low fosters aggression by a simple pro-dopaminergic mechanism.


Assuntos
Agressão/fisiologia , Encéfalo/diagnóstico por imagem , Monoaminoxidase/genética , Polimorfismo de Nucleotídeo Único , Encéfalo/metabolismo , Dopamina/metabolismo , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Tomografia por Emissão de Pósitrons , Adulto Jovem
18.
PLoS One ; 10(4): e0123476, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25894969

RESUMO

In order to assess the feasibility of amplicon-based parallel next generation sequencing (NGS) for the diagnosis of myeloproliferative neoplasms (MPN), we investigated multiplex-PCR of 212 amplicons covering genomic mutational hotspots in 48 cancer-related genes. Samples from 64 patients with MPN and five controls as well as seven (myeloid) cell lines were analyzed. Healthy donor and reactive erythrocytosis samples showed several frequent single-nucleotide polymorphisms (SNPs) but no known pathogenic mutation. Sequencing of the cell lines confirmed the presence of the known mutations. In the patient samples, JAK2 V617F was present in all PV, 4 of 10 ET, and 16 of 19 MF patients. The JAK2 V617F allele burden was different in the three groups (ET, 33+/-22%; PV 48+/-28% and MF 68+/- 29%). Further analysis detected both previously described and undescribed mutations (i.e., G12V NRAS, IDH1 R132H, E255G ABL, and V125G IDH1 mutations). One patient with lymphoid BC/Ph+ ALL who harbored a T315I ABL mutation and was treated with ponatinib was found to have developed a newly acquired V216M TP53 mutation (12% of transcripts) when becoming resistant to ponatinib. Ponatinib led to a decrease of ABL T315I positive transcripts from 47% before ponatinib treatment to 16% at the time of ponatinib resistance in this patient, suggesting that both TP53 and ABL mutations were present in the same clone and that the newly acquired TP53 mutation might have caused ponatinib resistance in this patient. In conclusion, amplicon-sequencing-based NGS allows simultaneous analysis of multiple MPN associated genes for diagnosis and during treatment and measurement of the mutant allele burden.


Assuntos
Neoplasias da Medula Óssea/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Transtornos Mieloproliferativos/genética , Alelos , Linhagem Celular Tumoral , Seguimentos , Humanos , Janus Quinase 2/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Controle de Qualidade
19.
BMC Nephrol ; 16: 22, 2015 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-25886171

RESUMO

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare but frequently severe disorder that is typically characterized by cystic kidneys and congenital hepatic fibrosis but displays pronounced phenotypic heterogeneity. ARPKD is among the most important causes for pediatric end stage renal disease and a leading reason for liver-, kidney- or combined liver kidney transplantation in childhood. The underlying pathophysiology, the mechanisms resulting in the observed clinical heterogeneity and the long-term clinical evolution of patients remain poorly understood. Current treatment approaches continue to be largely symptomatic and opinion-based even in most-advanced medical centers. While large clinical trials for the frequent and mostly adult onset autosomal dominant polycystic kidney diseases have recently been conducted, therapeutic initiatives for ARPKD are facing the challenge of small and clinically variable cohorts for which reliable end points are hard to establish. METHODS/DESIGN: ARegPKD is an international, mostly European, observational study to deeply phenotype ARPKD patients in a pro- and retrospective fashion. This registry study is conducted with the support of the German Society for Pediatric Nephrology (GPN) and the European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients (ESCAPE Network). ARegPKD clinically characterizes long-term ARPKD courses by a web-based approach that uses detailed basic data questionnaires in combination with yearly follow-up visits. Clinical data collection is accompanied by associated biobanking and reference histology, thus setting roots for future translational research. DISCUSSION: The novel registry study ARegPKD aims to characterize miscellaneous subcohorts and to compare the applied treatment options in a large cohort of deeply characterized patients. ARegPKD will thus provide evidence base for clinical treatment decisions and contribute to the pathophysiological understanding of this severe inherited disorder.


Assuntos
Bancos de Espécimes Biológicos/organização & administração , Falência Renal Crônica/diagnóstico , Rim Policístico Autossômico Recessivo/diagnóstico , Rim Policístico Autossômico Recessivo/terapia , Sistema de Registros , Adulto , Criança , Progressão da Doença , Europa (Continente) , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/terapia , Humanos , Internacionalidade , Internet , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/terapia , Masculino , Rim Policístico Autossômico Recessivo/epidemiologia , Controle de Qualidade , Projetos de Pesquisa , Sensibilidade e Especificidade , Índice de Gravidade de Doença
20.
Am J Hum Genet ; 96(1): 81-92, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25557784

RESUMO

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits ß-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC.


Assuntos
Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Via de Sinalização Wnt/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Cílios/genética , Cílios/patologia , Biologia Computacional , Proteínas Desgrenhadas , Éxons , Células HEK293 , Humanos , Rim/patologia , Camundongos , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Células NIH 3T3 , Fenótipo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Peixe-Zebra/genética , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
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