Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 966
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360805

RESUMO

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.


Assuntos
Anormalidades Múltiplas , Caseína Quinase I , Fissura Palatina , Exoftalmia , Proteínas da Matriz Extracelular , Variação Genética , Microcefalia , Osteosclerose , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Fissura Palatina/genética , Fissura Palatina/metabolismo , Fissura Palatina/mortalidade , Fissura Palatina/patologia , Exoftalmia/genética , Exoftalmia/metabolismo , Exoftalmia/mortalidade , Exoftalmia/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/mortalidade , Microcefalia/patologia , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/mortalidade , Osteosclerose/patologia
2.
Nat Metab ; 3(8): 1109-1124, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34385701

RESUMO

Zika virus (ZIKV) infection during pregnancy can cause microcephaly in newborns, yet the underlying mechanisms remain largely unexplored. Here, we reveal extensive and large-scale metabolic reprogramming events in ZIKV-infected mouse brains by performing a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics and metabolomics approaches. Our proteomics and metabolomics analyses uncover dramatic alteration of nicotinamide adenine dinucleotide (NAD+)-related metabolic pathways, including oxidative phosphorylation, TCA cycle and tryptophan metabolism. Phosphoproteomics analysis indicates that MAPK and cyclic GMP-protein kinase G signaling may be associated with ZIKV-induced microcephaly. Notably, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments, which confirm that boosting NAD+ by NAD+ or nicotinamide riboside supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. Nicotinamide riboside supplementation increases the brain and body weight as well as improves the survival in ZIKV-infected mice. Our study provides a comprehensive resource of biological data to support future investigations of ZIKV-induced microcephaly and demonstrates that metabolic alterations can be potentially exploited for developing therapeutic strategies.


Assuntos
Microcefalia/etiologia , Microcefalia/metabolismo , NAD/metabolismo , Infecção por Zika virus/complicações , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Células Cultivadas , Cromatografia Líquida , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Metabolômica , Camundongos , Microcefalia/patologia , Neurônios/metabolismo , Gravidez , Proteômica/métodos , Espectrometria de Massas em Tandem
3.
Eur J Med Genet ; 64(10): 104310, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34400370

RESUMO

MFSD2A, a member of the major facilitator superfamily (MFS), is a transmembrane transporter responsible for the uptake of specific essential fatty acids through the blood-brain barrier (BBB) to the brain. The transporter is crucial for early embryonic brain development and a major factor in the formation and maintenance of the BBB. Mfsd2a-knockout mice show a leakage of the BBB in early embryonic stages and develop a phenotype characterized by microcephaly, cognitive impairment, and anxiety. So far, homozygous or compound heterozygous MFSD2A mutations in humans have only been reported in 13 different families with a total of 28 affected individuals. The phenotypical spectrum of patients with MFSD2A variants is rather broad but all patients present with microcephaly and severe intellectual disability, absent or limited speech, and walking difficulties. Severely affected patients develop seizures and show brain malformations and have, above all, a profound developmental delay hardly reaching any developmental motor milestones. Here, we report on two unrelated individuals with novel homozygous variants in the MFSD2A gene, presenting with severe primary microcephaly, brain malformations, profound developmental delay, and epilepsy, including hypsarrhythmia. Our findings extend the mutational spectrum of the bi-allelic MFSD2A variants causing autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants emphasizing the role of MFSD2A in early brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Microcefalia/genética , Fenótipo , Simportadores/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Microcefalia/patologia , Mutação
4.
Eur J Med Genet ; 64(9): 104282, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34284163

RESUMO

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.


Assuntos
Agenesia do Corpo Caloso/genética , Axônios/patologia , Fatores de Transcrição Forkhead/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurogênese , Oligodendroglia/patologia , Feto Abortado/metabolismo , Feto Abortado/patologia , Adulto , Agenesia do Corpo Caloso/patologia , Axônios/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Encéfalo/patologia , Códon sem Sentido , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Microcefalia/patologia , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Oligodendroglia/metabolismo , Linhagem , Gravidez , Síndrome
5.
Genes (Basel) ; 12(5)2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066864

RESUMO

Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of ETFDH and PHGDH genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the ETFDH gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the PHGDH gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/genética , Flavoproteínas Transferidoras de Elétrons/genética , Proteínas Ferro-Enxofre/genética , Microcefalia/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Fosfoglicerato Desidrogenase/deficiência , Fosfoglicerato Desidrogenase/genética , Transtornos Psicomotores/genética , Convulsões/genética , Serina/deficiência , Erros Inatos do Metabolismo dos Carboidratos/sangue , Erros Inatos do Metabolismo dos Carboidratos/patologia , Pré-Escolar , Feminino , Humanos , Microcefalia/sangue , Microcefalia/patologia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/patologia , Mutação de Sentido Incorreto , Fosfoglicerato Desidrogenase/sangue , Transtornos Psicomotores/sangue , Transtornos Psicomotores/patologia , Convulsões/sangue , Convulsões/patologia , Serina/sangue
6.
Genes (Basel) ; 12(5)2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068194

RESUMO

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic-microcephaly primary hereditary (MCPH)-and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT-genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.


Assuntos
Genes Modificadores , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Hidrolases Anidrido Ácido/genética , Adulto , Antígenos/genética , Proteínas de Ciclo Celular/genética , Criança , Proteínas de Ligação a DNA/genética , Feminino , Heterozigoto , Humanos , Masculino , Microcefalia/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Linhagem , Fenótipo
7.
Eur J Med Genet ; 64(9): 104263, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34174466

RESUMO

INTRODUCTION: Biallelic variants in the SLC1A4 gene have been so far identified as a very rare cause of neurodevelopmental disorders with or without epilepsy and almost exclusively described in the Ashkenazi-Jewish population. PATIENTS AND METHODS: Here we present Czech patient with microcephaly, severe global developmental delay and intractable seizures whose condition remained undiagnosed despite access to clinical experience and standard diagnostic methods including examination with an epilepsy targeted NGS gene panel. RESULTS: Whole exome sequencing revealed a novel variant NM_003038.4:c.1370G > A p.(Arg457Gln) of the SLC1A4 gene in a homozygous state in the patient, and afterwards Sanger sequencing in both parents confirmed the biallelic origin of the variant. A variant in the same codon, but with a different amino acid exchange, was described previously in a patient that had a very similar phenotype, however, without epilepsy. CONCLUSION: Our data suggest that the SLC1A4 gene should be considered in the diagnosis of patients with severe, early onset neurodevelopmental impairment with epilepsy and encourage the analysis of SLC1A4 gene variants via targeted NGS gene panel or whole exome sequencing.


Assuntos
Sistema ASC de Transporte de Aminoácidos/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Criança , Homozigoto , Humanos , Masculino , Microcefalia/patologia , Mutação , Transtornos do Neurodesenvolvimento/patologia , Convulsões/patologia
8.
Eur J Med Genet ; 64(7): 104233, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33933664

RESUMO

Primary microcephaly (MCPH) is a rare neurogenic disorder with most cases being inherited in an autosomal recessive pattern. The present report is of a case of second gravid patient with recurrent fetal microcephaly with agenesis of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Maternal TORCH profile and amniotic fluid chromosomal microarray were normal. Following the termination of pregnancy, the autopsy evaluation has shown additional findings of evolving craniosynostosis, and semilobar holoprosencephaly. Whole exome sequencing done on fetal DNA from amniotic fluid, revealed a pathogenic compound heterozygous variant (NM_025009.5) c.2863C>T (p.Arg955Ter) in exon 22 and c.1372_1375del (p.Lys459SerfsTer2) in exon 11 of CEP135 gene: known to cause primary microcephaly-8; and both partners in the couple are heterozygous carriers for the same. With the identification of MCPH genes and with the availability of next-generation sequencing (NGS) based exome sequencing, a definitive prenatal diagnosis of primary microcephaly and also appropriate genetic counselling for the couple has become possible.


Assuntos
Proteínas de Transporte/genética , Microcefalia/genética , Feto Abortado/anormalidades , Adulto , Feminino , Heterozigoto , Humanos , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Fenótipo , Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma
9.
Genes (Basel) ; 12(4)2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921653

RESUMO

Type 2 congenital microcephaly (MCPH2) is a brain development disorder characterized by primary microcephaly with or without brain malformations. MCPH2 is caused by mutations in the WDR62 gene. We present three new patients with MCPH2 and compound heterozygous mutations in the WDR62 gene. In all the cases, the parents were healthy and unrelated. All children were clinically diagnosed with congenital microcephaly and retardation of motor and speech development. Sequencing results in the presented patients revealed five new variants in the WDR62 gene (c.4273C>T, c.1711_1712insTA, c.1777_1778delGA, c.1642+2T>G, c.194T>A) and one previously described in the German population (c.2864_2867delACAG). In two of the presented cases, variants in the SMAD4, DKC1, and ATRX genes were also found with unknown effects on the course of the disease. Moreover, in the article we collected and compared the most common clinical symptoms, dysmorphic features, and changes in radiographic examinations of the brain observed in 120 patients with recessive primary microcephaly type 2 caused by mutations in the WDR62 gene.


Assuntos
Proteínas de Ciclo Celular/genética , Malformações do Desenvolvimento Cortical/patologia , Microcefalia/patologia , Proteínas do Tecido Nervoso/genética , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/genética , Microcefalia/complicações , Microcefalia/genética , Mutação , Linhagem , Fenótipo
10.
Eur J Med Genet ; 64(7): 104225, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33872775

RESUMO

Ring X is a chromosomal anomaly mainly seen in females with turner syndrome and usually present in mosaic form with 45,X cells (45,X/46,X,r(X)) because of their mitotic instability. In males it is an extremely rare finding because large nullisomy for X chromosome material is likely not compatible with survival. Only two cases of male with ring chromosome X were previously reported. We report here a four-year-old male with ring chromosome X characterized using Karyotype, FISH and array CGH and presenting short stature, microcephaly and hypospadias. Molecular investigations showed 923 Kb terminal deletion on the pseudoautosomal region 1 (PAR1) including SHOX gene followed by a duplication of 2.4 Mb. The absence of functional nullisomy because of a second copy of deleted genes was present in chromosome Y PAR1 region may explain the compatibility with survival in our case of male with ring X. Short stature common with the two previously reported cases is likely related to SHOX gene deletion but also to the effect of "ring syndrome". However, hypospadias was not reported in the previous cases and can be due to the associated duplication outside PAR1 region including in particular PRKX gene coding for a protein involved in urogenital system morphogenesis.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos X/genética , Hipospadia/genética , Microcefalia/genética , Cromossomos em Anel , Pré-Escolar , Transtornos Cromossômicos/patologia , Deleção de Genes , Duplicação Gênica , Humanos , Hipospadia/patologia , Masculino , Microcefalia/patologia , Proteína de Homoeobox de Baixa Estatura/genética , Síndrome
11.
Am J Med Genet A ; 185(5): 1589-1597, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33682303

RESUMO

THG1L-associated autosomal recessive ataxia belongs to a group of disorders that occur due to abnormal mitochondrial tRNA modification. The product of THG1L is the tRNA-histidine guanylyltransferase 1-like enzyme that catalyzes the 3'-5"addition of guanine to the 5"-end of tRNA-histidine in the mitochondrion. To date, five individuals with homozygosity for p.(Val55Ala) in THG1L have been reported and presented with mild delays or normal development and cerebellar dysfunction. We present seven individuals with biallelic variants in THG1L. Three individuals were compound heterozygous for the p.(Cys51Trp) and p.(Val55Ala) variants and presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia. Four siblings were homozygous for the p.(Val55Ala) variant and presented with cerebellar ataxia with cerebellar vermis hypoplasia, dysarthria, mild developmental delays, and normal/near-normal cognition. All seven patients were of Ashkenazi Jewish descent. Carrier rates for the two variants were calculated in a cohort of 26,731 Ashkenazi Jewish individuals tested by the Dor Yeshorim screening program. The p.(Cys51Trp) variant is novel and was found in 40 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 668 (0.15%). The p.(Val55Ala) variant was found in 229 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 117 (0.85%). The individuals with compound heterozygosity of the p.(Val55Ala) and p.(Cys51Trp) variants expand the phenotypic spectrum of THG1L-related disorders to include severe epileptic encephalopathy. The individuals with homozygosity of the p.(V55A) variant further establish the associated mild and slowly progressive or nonprogressive neurodevelopmental phenotype.


Assuntos
Encefalopatias/genética , Ataxia Cerebelar/genética , Epilepsia/genética , Proteínas/genética , Adolescente , Alelos , Encefalopatias/complicações , Encefalopatias/patologia , Ataxia Cerebelar/complicações , Ataxia Cerebelar/patologia , Doenças Cerebelares/complicações , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epilepsia/complicações , Epilepsia/patologia , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Judeus/genética , Masculino , Microcefalia/complicações , Microcefalia/genética , Microcefalia/patologia , Mutação/genética , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Fenótipo , Irmãos
12.
Commun Biol ; 4(1): 358, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33742057

RESUMO

Centromere-associated protein-E (CENP-E) is a kinesin motor localizing at kinetochores. Although its mitotic functions have been well studied, it has been challenging to investigate direct consequences of CENP-E removal using conventional methods because CENP-E depletion resulted in mitotic arrest. In this study, we harnessed an auxin-inducible degron system to achieve acute degradation of CENP-E. We revealed a kinetochore-independent role for CENP-E that removes pericentriolar material 1 (PCM1) from centrosomes in late S/early G2 phase. After acute loss of CENP-E, centrosomal Polo-like kinase 1 (Plk1) localization is abrogated through accumulation of PCM1, resulting in aberrant phosphorylation and destabilization of centrosomes, which triggers shortened astral microtubules and oblique cell divisions. Furthermore, we also observed centrosome and cell division defects in cells from a microcephaly patient with mutations in CENPE. Orientation of cell division is deregulated in some microcephalic patients, and our unanticipated findings provide additional insights into how microcephaly can result from centrosomal defects.


Assuntos
Centrômero/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Microcefalia/metabolismo , Mitose , Epitélio Pigmentado da Retina/metabolismo , Antígenos/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Centrômero/genética , Centrômero/patologia , Proteínas Cromossômicas não Histona/genética , Humanos , Microcefalia/genética , Microcefalia/patologia , Mutação , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais
13.
J Allergy Clin Immunol ; 148(2): 599-611, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33662367

RESUMO

BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. OBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. METHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. RESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. CONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.


Assuntos
Cegueira Cortical , Forminas , Microcefalia , Doenças Mitocondriais , Convulsões , Imunodeficiência Combinada Severa , Adulto , Cegueira Cortical/genética , Cegueira Cortical/imunologia , Cegueira Cortical/patologia , Criança , Pré-Escolar , Feminino , Finlândia , Forminas/deficiência , Forminas/imunologia , Humanos , Masculino , Microcefalia/genética , Microcefalia/imunologia , Microcefalia/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Doenças Mitocondriais/patologia , Omã , Convulsões/genética , Convulsões/imunologia , Convulsões/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Síndrome
14.
Hum Genet ; 140(6): 945-955, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33709208

RESUMO

Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.


Assuntos
Transtornos da Insuficiência da Medula Óssea/diagnóstico , Disceratose Congênita/diagnóstico , Retardo do Crescimento Fetal/diagnóstico , Triagem de Portadores Genéticos/métodos , Deficiência Intelectual/diagnóstico , Microcefalia/diagnóstico , Telômero/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Doenças Assintomáticas , Transtornos da Insuficiência da Medula Óssea/genética , Transtornos da Insuficiência da Medula Óssea/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Disceratose Congênita/genética , Disceratose Congênita/patologia , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Microcefalia/genética , Microcefalia/patologia , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Análise de Sobrevida , Telômero/metabolismo , Homeostase do Telômero
15.
Am J Med Genet A ; 185(4): 1275-1281, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33527719

RESUMO

Individuals carrying biallelic loss-of-function mutations in PCDH12 have been reported with three different conditions: the diencephalic-mesencephalic junction dysplasia syndrome 1 (DMJDS1), a disorder characterized by global developmental delay, microcephaly, dystonia, and a midbrain malformation at the diencephalic-mesencephalic junction; cerebral palsy combined with a neurodevelopmental disorder; and cerebellar ataxia with retinopathy. We report an additional patient carrying a homozygous PCDH12 frameshift, whose anamnesis combines the most recurrent DMJDS1 clinical features, that is, global developmental delay, microcephaly, and ataxia, with exudative vitreoretinopathy. This case and previously published DMJDS1 patients presenting with nonspecific visual impairments and ophthalmic disorders suggest that ophthalmic alterations are an integral part of clinical features associated with PCDH12 loss-of-function.


Assuntos
Ataxia/genética , Caderinas/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Adolescente , Adulto , Ataxia/diagnóstico , Ataxia/patologia , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Diencéfalo/diagnóstico por imagem , Diencéfalo/patologia , Feminino , Homozigoto , Humanos , Mutação com Perda de Função/genética , Masculino , Microcefalia/diagnóstico , Microcefalia/patologia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Linhagem , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/genética , Doenças Retinianas/patologia
16.
Nat Commun ; 12(1): 833, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547280

RESUMO

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.


Assuntos
Deficiências do Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento , Microcefalia/genética , Micrognatismo/genética , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Adolescente , Sequência de Aminoácidos , Animais , Criança , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Embrião não Mamífero , Feminino , Humanos , Lisina/análogos & derivados , Lisina/genética , Lisina/metabolismo , Masculino , Microcefalia/metabolismo , Microcefalia/patologia , Micrognatismo/metabolismo , Micrognatismo/patologia , Fatores de Iniciação de Peptídeos/deficiência , Peptídeos/genética , Peptídeos/metabolismo , Biossíntese de Proteínas , Conformação Proteica , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Espermidina/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
Am J Med Genet A ; 185(4): 1204-1210, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33442900

RESUMO

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.


Assuntos
Pálpebras/anormalidades , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteína Proto-Oncogênica N-Myc/genética , Fístula Traqueoesofágica/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Pálpebras/patologia , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/patologia , Masculino , Microcefalia/complicações , Microcefalia/patologia , Fenótipo , Sindactilia/complicações , Sindactilia/genética , Sindactilia/patologia , Fístula Traqueoesofágica/complicações , Fístula Traqueoesofágica/patologia
18.
Viruses ; 13(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466404

RESUMO

Upper respiratory obstruction is a common sequela in children with Zika-related microcephaly (ZRM). As a cross-sectional analysis nested in a cohort study, this study aims to investigate the prevalence of adenoid hypertrophy (AH) in children with ZRM and symptoms of respiratory obstruction. The data were collected in the first three years of life from children with ZRM who were followed in two reference centers for otorhinolaryngological care of patients with congenital Zika syndrome. Out of 92 children with confirmed ZRM, 57 were evaluated by nasopharyngoscopy after presenting with upper respiratory obstruction symptoms. In this study, 31 of the 57 (54%) children with ZRM who were evaluated had obstructive AH. Thirteen children with obstructive AH were submitted to surgery, which resulted in the complete resolution of symptoms for 11, partial resolution in 1, and no improvement in 1. No evidence of direct involvement by Zika virus (ZIKV) infection in the adenoid tissues was demonstrated by histology or immunohistochemistry. Our results suggest that there is a high prevalence and early presentation of AH in children with ZRM, with consequent upper airway obstruction causing upper airway obstructive disorder, secretory otitis media, and dysphagia.


Assuntos
Tonsila Faríngea/patologia , Microcefalia/epidemiologia , Infecção por Zika virus/epidemiologia , Brasil , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Hipertrofia/complicações , Hipertrofia/epidemiologia , Lactente , Masculino , Microcefalia/patologia , Microcefalia/virologia , Prevalência , Infecção por Zika virus/patologia
19.
Magn Reson Imaging ; 76: 26-38, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33010377

RESUMO

G Protein-Coupled Receptor Kinase-Interacting Protein-1 (GIT1) regulates neuronal functions, including cell and axon migration and synapse formation and maintenance, and GIT1 knockout (KO) mice exhibit learning and memory deficits. We noted that male and female GIT1-KO mice exhibit neuroimaging phenotypes including microcephaly, and altered cortical layering, with a decrease in neuron density in cortical layer V. Micro-CT and magnetic resonance microscopy (MRM) were used to identify morphometric phenotypes for the skulls and throughout the GIT1-KO brains. High field MRM of actively-stained mouse brains from GIT1-KO and wild type (WT) controls (n = 6 per group) allowed segmenting 37 regions, based on co-registration to the Waxholm Space atlas. Overall brain size in GIT1-KO mice was ~32% smaller compared to WT controls. After correcting for brain size, several regions were significantly different in GIT1-KO mice relative to WT, including the gray matter of the ventral thalamic nuclei and the rest of the thalamus, the inferior colliculus, and pontine nuclei. GIT1-KO mice had reduced volume of white matter tracts, most notably in the anterior commissure (~26% smaller), but also in the cerebral peduncle, fornix, and spinal trigeminal tract. On the other hand, the basal ganglia appeared enlarged in GIT1-KO mice, including the globus pallidus, caudate putamen, and particularly the accumbens - supporting a possible vulnerability to addiction. Volume based morphometry based on high-resolution MRM (21.5 µm isotropic voxels) was effective in detecting overall, and local differences in brain volumes in GIT1-KO mice, including in white matter tracts. The reduced relative volume of specific brain regions suggests a critical, but not uniform, role for GIT1 in brain development, conducive to brain microcephaly, and aberrant connectivity.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proteínas de Ciclo Celular/deficiência , Proteínas Ativadoras de GTPase/deficiência , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Neuroimagem , Animais , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Técnicas de Inativação de Genes , Masculino , Camundongos , Microcefalia/genética , Neurônios/metabolismo , Neurônios/patologia , Microtomografia por Raio-X
20.
FEBS J ; 288(1): 190-211, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32248620

RESUMO

Warburg micro syndrome (WMS) is a hereditary autosomal neuromuscular disorder in humans caused by mutations in Rab18, Rab3GAP1, or Rab3GAP2 genes. Rab3GAP1/2 forms a heterodimeric complex, which acts as a guanosine nucleotide exchange factor and activates Rab18. Although the genetic causes of WMS are known, it is still unclear whether loss of the Rab3GAP-Rab18 module affects neuronal or muscle cell physiology or both, and how. In this work, we characterize a Rab3GAP2 mutant Drosophila line to establish a novel animal model for WMS. Similarly to symptoms of WMS, loss of Rab3GAP2 leads to highly decreased motility in Drosophila that becomes more serious with age. We demonstrate that these mutant flies are defective for autophagic degradation in multiple tissues including fat cells and muscles. Loss of Rab3GAP-Rab18 module members leads to perturbed autolysosome morphology due to destabilization of Rab7-positive autophagosomal and late endosomal compartments and perturbation of lysosomal biosynthetic transport. Importantly, overexpression of UVRAG or loss of Atg14, two alternative subunits of the Vps34/PI3K (vacuole protein sorting 34/phosphatidylinositol 3-kinase) complexes in fat cells, mimics the autophagic phenotype of Rab3GAP-Rab18 module loss. We find that GTP-bound Rab18 binds to Atg6/Beclin1, a permanent subunit of Vps34 complexes. Finally, we show that Rab3GAP2 and Rab18 are present on autophagosomal and autolysosomal membranes and colocalize with Vps34 Complex I subunits. Our data suggest that the Rab3GAP-Rab18 module regulates autolysosomal maturation through its interaction with the Vps34 Complex I, and perturbed autophagy due to loss of the Rab3GAP-Rab18 module may contribute to the development of WMS.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Classe III de Fosfatidilinositol 3-Quinases/genética , Córnea/anormalidades , Proteínas de Drosophila/genética , Hipogonadismo/genética , Deficiência Intelectual/genética , Lisossomos/metabolismo , Microcefalia/genética , Atrofia Óptica/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Catarata/genética , Catarata/metabolismo , Catarata/patologia , Classe III de Fosfatidilinositol 3-Quinases/deficiência , Córnea/metabolismo , Córnea/patologia , Modelos Animais de Doenças , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Regulação da Expressão Gênica , Humanos , Hipogonadismo/metabolismo , Hipogonadismo/patologia , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Lisossomos/patologia , Microcefalia/metabolismo , Microcefalia/patologia , Músculos/metabolismo , Músculos/patologia , Neurônios/metabolismo , Neurônios/patologia , Atrofia Óptica/metabolismo , Atrofia Óptica/patologia , Ligação Proteica , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas rab de Ligação ao GTP/deficiência , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab3 de Ligação ao GTP/deficiência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...