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[PMID]:29451896
[Au] Autor:Ji H; Li D; Wu Y; Zhang Q; Gu Q; Xie H; Ji T; Wang H; Zhao L; Zhao H; Yang Y; Feng H; Xiong H; Ji J; Yang Z; Kou L; Li M; Bao X; Chang X; Zhang Y; Li L; Li H; Niu Z; Wu X; Xiao J; Jiang Y; Wang J
[Ad] Endereço:Department of Pediatrics, Peking University First Hospital, Beijing, China.
[Ti] Título:Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients.
[So] Source:PLoS One;13(2):e0188869, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population. METHODS: 119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing. RESULTS: Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively. SIGNIFICANCE: This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.
[Mh] Termos MeSH primário: Heterogeneidade Genética
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/epidemiologia
[Mh] Termos MeSH secundário: China/epidemiologia
Bandeamento Cromossômico
Feminino
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia
Seres Humanos
Lactente
Recém-Nascido
Cariotipagem
Imagem por Ressonância Magnética
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180217
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188869


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[PMID]:28931644
[Au] Autor:Hamilton EMC; Bertini E; Kalaydjieva L; Morar B; Dojcáková D; Liu J; Vanderver A; Curiel J; Persoon CM; Diodato D; Pinelli L; van der Meij NL; Plecko B; Blaser S; Wolf NI; Waisfisz Q; Abbink TEM; van der Knaap MS; Recessive H-ABC Research Group
[Ad] Endereço:From the Department of Child Neurology (E.M.C.H., N.I.W., T.E.M.A., M.S.v.d.K.), Amsterdam Neuroscience (E.M.C.H., N.I.W., T.E.M.A., M.S.v.d.K.), Department of Clinical Genetics (C.M.P., Q.W.), Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (M.S.v.d.K.), VU Univer
[Ti] Título: founder mutation in the Roma population causes recessive variant of H-ABC.
[So] Source:Neurology;89(17):1821-1828, 2017 Oct 24.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for mutations. METHODS: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. RESULTS: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of . Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines. CONCLUSIONS: encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a gene defect with a disease and sheds new light on possible UFM1 functional networks.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Acídicos/deficiência
Antiporters/deficiência
Gânglios da Base/patologia
Cerebelo/patologia
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Doenças Mitocondriais/genética
Polimorfismo de Nucleotídeo Único/genética
Proteínas/genética
Transtornos Psicomotores/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Sistemas de Transporte de Aminoácidos Acídicos/genética
Antiporters/genética
Atrofia/etiologia
Gânglios da Base/diagnóstico por imagem
Linhagem Celular Tumoral/patologia
Cerebelo/diagnóstico por imagem
Criança
Pré-Escolar
Análise Mutacional de DNA
Saúde da Família
Feminino
Células HeLa
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem
Seres Humanos
Processamento de Imagem Assistida por Computador
Itália
Imagem por Ressonância Magnética
Masculino
Doenças Mitocondriais/complicações
Doenças Mitocondriais/diagnóstico por imagem
Transtornos Psicomotores/complicações
Transtornos Psicomotores/diagnóstico por imagem
Transfecção
Tubulina (Proteína)/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Acidic); 0 (Antiporters); 0 (Proteins); 0 (TUBB4A protein, human); 0 (Tubulin); 0 (UFM1 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171105
[Lr] Data última revisão:
171105
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000004578


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[PMID]:28575651
[Au] Autor:Chelban V; Patel N; Vandrovcova J; Zanetti MN; Lynch DS; Ryten M; Botía JA; Bello O; Tribollet E; Efthymiou S; Davagnanam I; Bashiri FA; Wood NW; Rothman JE; Alkuraya FS; Houlden H; SYNAPSE Study Group
[Ad] Endereço:Department of Molecular Neuroscience, University College London, London WC1N 3BG, UK; Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Toma Ciorba 1, 2052 Chisinau, Republic of Moldova. Electronic address: v.chelban@ucl.ac.uk.
[Ti] Título:Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.
[So] Source:Am J Hum Genet;100(6):969-977, 2017 Jun 01.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Acídicos/deficiência
Antiporters/deficiência
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Proteínas de Homeodomínio/genética
Deficiência Intelectual/complicações
Deficiência Intelectual/genética
Doenças Mitocondriais/complicações
Doenças Mitocondriais/genética
Espasticidade Muscular/complicações
Espasticidade Muscular/genética
Mutação/genética
Atrofia Óptica/complicações
Atrofia Óptica/genética
Transtornos Psicomotores/complicações
Transtornos Psicomotores/genética
Ataxias Espinocerebelares/complicações
Ataxias Espinocerebelares/genética
[Mh] Termos MeSH secundário: Adulto
Sequência de Aminoácidos
Sistemas de Transporte de Aminoácidos Acídicos/genética
Antiporters/genética
Encéfalo/embriologia
Encéfalo/metabolismo
Criança
Feminino
Redes Reguladoras de Genes
Proteínas de Homeodomínio/química
Seres Humanos
Lactente
Masculino
Linhagem
Fenótipo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Acidic); 0 (Antiporters); 0 (Homeodomain Proteins); 0 (NKX6-2 protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE


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[PMID]:28429368
[Au] Autor:Juaristi I; García-Martín ML; Rodrigues TB; Satrústegui J; Llorente-Folch I; Pardo B
[Ad] Endereço:Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Madrid, Spain.
[Ti] Título:ARALAR/AGC1 deficiency, a neurodevelopmental disorder with severe impairment of neuronal mitochondrial respiration, does not produce a primary increase in brain lactate.
[So] Source:J Neurochem;142(1):132-139, 2017 Jul.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ARALAR/AGC1 (aspartate-glutamate mitochondrial carrier 1) is an important component of the NADH malate-aspartate shuttle (MAS). AGC1-deficiency is a rare disease causing global cerebral hypomyelination, developmental arrest, hypotonia, and epilepsy (OMIM ID #612949); the aralar-KO mouse recapitulates the major findings in humans. This study was aimed at understanding the impact of ARALAR-deficiency in brain lactate levels as a biomarker. We report that lactate was equally abundant in wild-type and aralar-KO mouse brain in vivo at postnatal day 17. We find that lactate production upon mitochondrial blockade depends on up-regulation of lactate formation in astrocytes rather than in neurons. However, ARALAR-deficiency decreased cell respiration in neurons, not astrocytes, which maintained unchanged respiration and lactate production. As the primary site of ARALAR-deficiency is neuronal, this explains the lack of accumulation of brain lactate in ARALAR-deficiency in humans and mice. On the other hand, we find that the cytosolic and mitochondrial components of the glycerol phosphate shuttle are present in astrocytes with similar activities. This suggests that glycerol phosphate shuttle is the main NADH shuttle in astrocytes and explains the absence of effects of ARALAR-deficiency in these cells.
[Mh] Termos MeSH primário: Agrecanas/genética
Agrecanas/metabolismo
Sistemas de Transporte de Aminoácidos Acídicos/deficiência
Antiporters/deficiência
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Ácido Láctico/metabolismo
Mitocôndrias/genética
Mitocôndrias/metabolismo
Doenças Mitocondriais/genética
Doenças do Sistema Nervoso/genética
Doenças do Sistema Nervoso/metabolismo
Neurônios/metabolismo
Transtornos Psicomotores/genética
[Mh] Termos MeSH secundário: Sistemas de Transporte de Aminoácidos Acídicos/genética
Animais
Antiporters/genética
Astrócitos/metabolismo
Química Encefálica/genética
Glucose/metabolismo
Glucosefosfato Desidrogenase/genética
Glucosefosfato Desidrogenase/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Consumo de Oxigênio/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agc1 protein, mouse); 0 (Aggrecans); 0 (Amino Acid Transport Systems, Acidic); 0 (Antiporters); 33X04XA5AT (Lactic Acid); EC 1.1.1.49 (Glucosephosphate Dehydrogenase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14047


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[PMID]:28407788
[Au] Autor:Choquet K; Yang S; Moir RD; Forget D; Larivière R; Bouchard A; Poitras C; Sgarioto N; Dicaire MJ; Noohi F; Kennedy TE; Rochford J; Bernard G; Teichmann M; Coulombe B; Willis IM; Kleinman CL; Brais B
[Ad] Endereço:Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada.
[Ti] Título:Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation.
[So] Source:Mol Brain;10(1):13, 2017 04 13.
[Is] ISSN:1756-6606
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.
[Mh] Termos MeSH primário: Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Mutação/genética
Bainha de Mielina/metabolismo
RNA Polimerase III/genética
[Mh] Termos MeSH secundário: Animais
Cerebelo/patologia
Cerebelo/fisiopatologia
Técnicas de Introdução de Genes
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia
Homozigoto
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Atividade Motora
Células de Purkinje/metabolismo
Células de Purkinje/patologia
RNA Polimerase III/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.7.6 (RNA Polymerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.1186/s13041-017-0294-y


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[PMID]:28378817
[Au] Autor:O'Brien A; Marshall CR; Blaser S; Ray PN; Yoon G
[Ad] Endereço:Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
[Ti] Título:Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.
[So] Source:Eur J Hum Genet;25(6):775-778, 2017 Jun.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations of the cystatin B gene (CSTB; OMIM 601145) are known to cause Unverricht-Lundborg disease or progressive myoclonic epilepsy-1A (EPM1A, MIM #254800). Most patients are homozygous for an expanded (>30) dodecamer repeat in the promoter region of CSTB, or are compound heterozygotes for the dodecamer repeat and a point mutation. We report two adolescent sisters born to consanguineous parents of Sri Lankan descent who presented with profound global developmental delay, microcephaly, cortical blindness and axial hypotonia with appendicular hypertonia. Neither sibling ever developed head control, independent sitting or ambulation, and never developed speech. The elder sister had a seizure disorder. Both sisters had profound microcephaly and distinct facial features. On serial brain imaging, they had progressive atrophy of the corpus callosum and supratentorial brain, and diffuse hypomyelination with progressive loss of myelin signal. Exome sequencing revealed both siblings to be homozygous for a c.218dupT (p.His75Serfs*2) mutation in exon 3 of CSTB. The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein.
[Mh] Termos MeSH primário: Cegueira Cortical/genética
Cistatina B/genética
Deficiências do Desenvolvimento/genética
Mutação da Fase de Leitura
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Microcefalia/genética
[Mh] Termos MeSH secundário: Adolescente
Cegueira Cortical/diagnóstico
Criança
Corpo Caloso/diagnóstico por imagem
Corpo Caloso/patologia
Deficiências do Desenvolvimento/diagnóstico
Feminino
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico
Homozigoto
Seres Humanos
Masculino
Microcefalia/diagnóstico
Bainha de Mielina/patologia
Linhagem
Síndrome
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CSTB protein, human); 88844-95-5 (Cystatin B)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2017.39


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[PMID]:28000699
[Au] Autor:Vasilescu C; Isohanni P; Palomäki M; Pihko H; Suomalainen A; Carroll CJ
[Ad] Endereço:Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
[Ti] Título:Absence of Hikeshi, a nuclear transporter for heat-shock protein HSP70, causes infantile hypomyelinating leukoencephalopathy.
[So] Source:Eur J Hum Genet;25(3):366-370, 2017 Feb.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Genetic leukoencephalopathies are a heterogeneous group of central nervous system disorders with white matter involvement. In a Finnish patient, we identified a novel homozygous disease-causing variant in HIKESHI, c.11G>C, p.(Cys4Ser), leading to hypomyelinating leukoencephalopathy with periventricular cysts and vermian atrophy. A founder Ashkenazi-Jewish disease-causing variant recently linked Hikeshi and its heat-shock protective function to leukoencephalopathy. In our patient, clinical features of lower limb spasticity, optic atrophy, nystagmus, and severe developmental delay were similar to reported patients. Additional features included vermian atrophy, epileptic seizures, and an ovarian tumor. Structural modeling and protein analyses revealed that modified interactions inside Hikeshi's hydrophobic pockets induce protein instability. The patient's cells showed impaired nuclear translocation of HSP70 during heat shock, and decreased ERO1-Lα, an endoplasmic reticulum (ER) oxidoreductase. Overall, we show that: (1) the clinical spectrum associated with Hikeshi deficiency extends to leukoencephalopathy with vermian atrophy and epilepsy; (2) the cellular disease process involves both nuclear chaperone and ER functions.
[Mh] Termos MeSH primário: Proteínas de Transporte/genética
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Proteínas de Transporte/química
Núcleo Celular
Células Cultivadas
Proteínas de Choque Térmico HSP70/metabolismo
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico
Seres Humanos
Lactente
Glicoproteínas de Membrana/metabolismo
Oxirredutases/metabolismo
Estabilidade Proteica
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (HSP70 Heat-Shock Proteins); 0 (Membrane Glycoproteins); 0 (hikeshi protein, human); EC 1.- (ERO1L protein, human); EC 1.- (Oxidoreductases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2016.189


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[PMID]:27860360
[Au] Autor:Meng L; Donti T; Xia F; Niu Z; Al Shamsi A; Hertecant J; Al-Jasmi F; Gibson JB; Nagakura H; Zhang J; He W; Eng C; Yang Y; Elsea SH
[Ad] Endereço:Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
[Ti] Título:Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy.
[So] Source:Am J Med Genet A;173(2):460-470, 2017 Feb.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Homozigoto
Microcefalia/diagnóstico
Microcefalia/genética
Mutação
Pirrolina Carboxilato Redutases/genética
[Mh] Termos MeSH secundário: Adolescente
Alelos
Substituição de Aminoácidos
Encéfalo/anormalidades
Criança
Pré-Escolar
Códon
Análise Mutacional de DNA
Exoma
Feminino
Estudos de Associação Genética
Gráficos de Crescimento
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Metabolômica/métodos
Linhagem
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Codon); EC 1.5.1.- (PYCR2 protein, human); EC 1.5.1.- (Pyrroline Carboxylate Reductases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161119
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.38049


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[PMID]:27564080
[Au] Autor:Kevelam SH; Steenweg ME; Srivastava S; Helman G; Naidu S; Schiffmann R; Blaser S; Vanderver A; Wolf NI; van der Knaap MS
[Ad] Endereço:Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands.
[Ti] Título:Update on Leukodystrophies: A Historical Perspective and Adapted Definition.
[So] Source:Neuropediatrics;47(6):349-354, 2016 Dec.
[Is] ISSN:1439-1899
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.
[Mh] Termos MeSH primário: Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central
[Mh] Termos MeSH secundário: Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/história
História do Século XIX
História do Século XX
História do Século XXI
Seres Humanos
RNA Polimerase III/genética
Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética
[Pt] Tipo de publicação:HISTORICAL ARTICLE; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Granulocyte-Macrophage Colony-Stimulating Factor); EC 2.7.7.6 (POLR3A protein, human); EC 2.7.7.6 (RNA Polymerase III)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160827
[St] Status:MEDLINE


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[PMID]:27535217
[Au] Autor:Thiffault I; Bernard G
[Ad] Endereço:Children's Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, MO, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
[Ti] Título:Expert opinion and caution are imperative for interpretation of next generation sequencing data.
[So] Source:Eur J Med Genet;59(10):519-21, 2016 Oct.
[Is] ISSN:1878-0849
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:We comment on the recent publication by Khalifa and Naffa who are reporting a young girl with variants in both WDR45 and POLR3A, which they state contribute to her clinical manifestations. We are arguing in this letter that the clinical, MRI, and genetics findings are not compatible with 4H leukodystrophy and that this patient is not affected by this condition.
[Mh] Termos MeSH primário: Proteínas de Transporte/genética
Prova Pericial
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
RNA Polimerase III/genética
[Mh] Termos MeSH secundário: Feminino
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Imagem por Ressonância Magnética
Mutação
Análise de Sequência de DNA
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (WDR45 protein, human); EC 2.7.7.6 (POLR3A protein, human); EC 2.7.7.6 (RNA Polymerase III)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160819
[St] Status:MEDLINE



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