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1.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

2.
PLoS Genet ; 11(3): e1005050, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25749076

RESUMO

Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology-or homeology-driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.


Assuntos
Duplicação Gênica , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Pontos de Quebra do Cromossomo , Inversão Cromossômica , Dosagem de Genes , Humanos
3.
J Neurosci Res ; 92(12): 1723-32, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25156430

RESUMO

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder of the central nervous system (CNS) caused by a wide variety of mutations affecting proteolipid protein 1 (PLP1). We assessed the effects of PLP1 mutations on water diffusion in CNS white matter by using diffusion tensor imaging. Twelve patients with different PLP1 point mutations encompassing a range of clinical phenotypes were analyzed, and the results were compared with a group of 12 age-matched controls. The parallel (λ// ), perpendicular (λ⊥ ), and apparent diffusion coefficients (ADC) and fractional anisotropy were measured in both limbs of the internal capsule, the genu and splenium of corpus callosum, the base of the pons, and the cerebral peduncles. The mean ADC and λ⊥ in the PMD patient group were both significantly increased in all selected structures, except for the base of the pons, compared with controls. PMD patients with the most severe disease, however, had a significant increase of both λ// and λ⊥ . In contrast, more mildly affected patients had much smaller changes in λ// and λ⊥ . These data suggest that myelin, the structure responsible in part for the λ⊥ barrier, is the major site of disease pathogenesis in this heterogeneous group of patients. Axons, in contrast, the structures mainly responsible for λ// , are much less affected, except within the subgroup of patients with the most severe disease. Clinical disability in patients with PLP1 point mutation is thus likely determined by the extent of pathological involvement of both myelin and axons, with alterations of both structures causing the most severe disease. © 2014 Wiley Periodicals, Inc.


Assuntos
Encéfalo/patologia , Imagem de Tensor de Difusão , Mutação/genética , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/patologia , Substância Branca/patologia , Adolescente , Adulto , Pedúnculo Cerebral/patologia , Criança , Pré-Escolar , Corpo Caloso/patologia , Avaliação da Deficiência , Humanos , Cápsula Interna/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Hum Mol Genet ; 23(20): 5464-78, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24890387

RESUMO

Alternative splicing of the proteolipid protein 1 gene (PLP1) produces two forms, PLP1 and DM20, due to alternative use of 5' splice sites with the same acceptor site in intron 3. The PLP1 form predominates in central nervous system RNA. Mutations that reduce the ratio of PLP1 to DM20, whether mutant or normal protein is formed, result in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We investigated the ability of sequences throughout PLP1 intron 3 to regulate alternative splicing using a splicing minigene construct transfected into the oligodendrocyte cell line, Oli-neu. Our data reveal that the alternative splice of PLP1 is regulated by a long-distance interaction between two highly conserved elements that are separated by 581 bases within the 1071-base intron 3. Further, our data suggest that a base-pairing secondary structure forms between these two elements, and we demonstrate that mutations of either element designed to destabilize the secondary structure decreased the PLP1/DM20 ratio, while swap mutations designed to restore the structure brought the PLP1/DM20 ratio to near normal levels. Sequence analysis of intron 3 in families with clinical symptoms of PMD who did not have coding-region mutations revealed mutations that segregated with disease in three families. We showed that these patient mutations, which potentially destabilize the secondary structure, also reduced the PLP1/DM20 ratio. This is the first report of patient mutations causing disease by disruption of a long-distance intronic interaction controlling alternative splicing. This finding has important implications for molecular diagnostics of PMD.


Assuntos
Processamento Alternativo , Íntrons , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , RNA Mensageiro/química , Pareamento de Bases , Linhagem Celular , Feminino , Humanos , Masculino , Modelos Moleculares , Mutação , Proteína Proteolipídica de Mielina/metabolismo , Conformação de Ácido Nucleico , Oligodendroglia/metabolismo , Linhagem , RNA Mensageiro/metabolismo , Análise de Sequência de DNA
5.
J Neurol Sci ; 335(1-2): 75-81, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24139698

RESUMO

OBJECTIVE: To determine whether quantitative measure of magnetic resonance imaging data from patients with the inherited leukodystrophy, Pelizaeus-Merzbacher disease (PMD) correlates with clinical severity or progression. METHODS: In our current work we have analyzed the clinical phenotypes and MRI scans of 51 male patients with PMD and 10 female carriers for whom the PLP1 genotype had been determined. In addition, we developed a 32-point functional disability scoring (FDS) system for PMD, and validated it for inter-rater reliability. Using conventional T1- and T2-weighted MRI images of the whole brain, we measured white matter and total brain volume (WMV and TBV), inter-caudate ratio (ICR), and corpus callosum area. RESULTS: There was a significant positive correlation of FDS with white matter fraction (WMV/TBV) and corpus callosum area. Also, when applying a median split based on FDS, patients with lower FDS showed reduced white matter fraction and corpus callosum area, and increased ICR compared to patients with relatively higher FDS, regardless of age. CONCLUSION: Although this patient population is heterogeneous, with multiple genetic and molecular mechanisms causing PMD, these data imply that white matter atrophy is a major pathological determinant of the clinical disability in most patients. Development of reliable non-invasive quantitative biomarkers of disease activity would be useful not only for following the natural history of the disease, but also raising the potential for evaluating future therapies.


Assuntos
Pessoas com Deficiência , Doenças do Sistema Nervoso/etiologia , Doença de Pelizaeus-Merzbacher/complicações , Adolescente , Adulto , Encéfalo/patologia , Criança , Pré-Escolar , Corpo Caloso/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteína Proteolipídica de Mielina/genética , Fibras Nervosas Mielinizadas/patologia , Doença de Pelizaeus-Merzbacher/genética , Adulto Jovem
6.
Hum Mutat ; 34(6): 860-3, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23483706

RESUMO

The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders.


Assuntos
Proteínas de Ligação ao GTP/genética , Genes Dominantes , Genes Ligados ao Cromossomo X , Proteínas de Membrana/genética , Mutação , Linhagem , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Proteínas de Ligação ao GTP/química , Humanos , Masculino , Proteínas de Membrana/química , Dados de Sequência Molecular , Alinhamento de Sequência
7.
Semin Neurol ; 32(1): 62-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22422208

RESUMO

The purpose of this article is to present contemporary information on the clinical and molecular diagnosis and the treatment of Pelizaeus-Merzbacher's disease (PMD) and related leukodystrophies. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. A diffuse pattern of hypomyelination is seen on magnetic resonance imaging (MRI) of PMD/SPG2 patients. A similar constellation of signs and pattern of hypomyelination lead to the autosomal recessive disease called Pelizaeus-Merzbacher-like disease 1 (PMLD1) and the less-severe spastic paraplegia 44 (SPG44), caused by mutations of the gap junction protein, gamma-2 gene (GJC2), formerly known as the gap junction protein, α-12 gene (GJA12). Magnetic resonance spectroscopy (MRS) and brainstem auditory evoked potentials (BAEP) may assist with differential clinical diagnosis of PMD and PMLD1. Supportive therapy for patients with PMD/SPG2 and PMLD1/SPG44 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.


Assuntos
Doenças Desmielinizantes/genética , Paraplegia/genética , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/genética , Doenças Desmielinizantes/diagnóstico , Feminino , Humanos , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação/genética , Paraplegia/diagnóstico , Doença de Pelizaeus-Merzbacher/terapia
8.
Hum Mol Genet ; 21(8): 1794-807, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22210628

RESUMO

ATP7A is a P-type ATPase that regulates cellular copper homeostasis by activity at the trans-Golgi network (TGN) and plasma membrane (PM), with the location normally governed by intracellular copper concentration. Defects in ATP7A lead to Menkes disease or its milder variant, occipital horn syndrome or to a newly discovered condition, ATP7A-related distal motor neuropathy (DMN), for which the precise pathophysiology has been obscure. We investigated two ATP7A motor neuropathy mutations (T994I, P1386S) previously associated with abnormal intracellular trafficking. In the patients' fibroblasts, total internal reflection fluorescence microscopy indicated a shift in steady-state equilibrium of ATP7A(T994I) and ATP7A(P1386S), with exaggerated PM localization. Transfection of Hek293T cells and NSC-34 motor neurons with the mutant alleles tagged with the Venus fluorescent protein also revealed excess PM localization. Endocytic retrieval of the mutant alleles from the PM to the TGN was impaired. Immunoprecipitation assays revealed an abnormal interaction between ATP7A(T994I) and p97/VCP, an ubiquitin-selective chaperone which is mutated in two autosomal dominant forms of motor neuron disease: amyotrophic lateral sclerosis and inclusion body myopathy with early-onset Paget disease and fronto-temporal dementia. Small-interfering RNA (SiRNA) knockdown of p97/VCP corrected ATP7A(T994I) mislocalization. Flow cytometry documented that non-permeabilized ATP7A(P1386S) fibroblasts bound a carboxyl-terminal ATP7A antibody, consistent with relocation of the ATP7A di-leucine endocytic retrieval signal to the extracellular surface and partially destabilized insertion of the eighth transmembrane helix. Our findings illuminate the mechanisms underlying ATP7A-related DMN and establish a link between p97/VCP and genetically distinct forms of motor neuron degeneration.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Ciclo Celular/metabolismo , Membrana Celular/metabolismo , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/metabolismo , Adenosina Trifosfatases/química , Alelos , Proteínas de Transporte de Cátions/química , ATPases Transportadoras de Cobre , Endocitose , Fibroblastos , Células HEK293 , Humanos , Neurônios Motores/metabolismo , Mutação , Ligação Proteica , Estrutura Secundária de Proteína , Transporte Proteico , Proteína com Valosina , Rede trans-Golgi/metabolismo
9.
J Neurol Sci ; 314(1-2): 130-7, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22050953

RESUMO

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis.


Assuntos
Axônios/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Esferoides Celulares/patologia , Adulto , Autopsia , Biópsia , Encéfalo/patologia , Transtornos Cognitivos/etiologia , Diagnóstico Diferencial , Erros de Diagnóstico , Evolução Fatal , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Leucoencefalopatias/diagnóstico , Imagem por Ressonância Magnética , Transtornos Mentais/etiologia , Transtornos dos Movimentos/etiologia , Neuroimagem , Estudos Retrospectivos
10.
Glia ; 59(10): 1414-34, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21598311

RESUMO

Aspartoacylase (ASPA) catalyzes deacetylation of N-acetylaspartate (NAA) to generate acetate and aspartate. Mutations in the gene for ASPA lead to reduced acetate availability in the CNS during development resulting in the fatal leukodystrophy Canavan disease. Highly specific polyclonal antibodies to ASPA were used to examine CNS expression in adult rats. In white matter, ASPA expression was associated with oligodendrocyte cell bodies, nuclei, and some processes, but showed a dissimilar distribution pattern to myelin basic protein and oligodendrocyte specific protein. Microglia expressed ASPA in all CNS regions examined, as did epiplexus cells of the choroid plexus. Pial and ependymal cells and some endothelial cells were ASPA positive, as were unidentified cellular nuclei throughout the CNS. Astrocytes did not express ASPA in their cytoplasm. In some fiber pathways and nerves, particularly in the brainstem and spinal cord, the axoplasm of many neuronal fibers expressed ASPA, as did some neurons. Acetyl coenzyme A synthase immunoreactivity was also observed in the axoplasm of many of the same fiber pathways and nerves. All ASPA-immunoreactive elements were unstained in brain sections from tremor rats, an ASPA-null mutant. The strong expression of ASPA in oligodendrocyte cell bodies is consistent with a lipogenic role in myelination. Strong ASPA expression in cell nuclei is consistent with a role for NAA-derived acetate in nuclear acetylation reactions, including histone acetylation. Expression of ASPA in microglia may indicate a role in lipid synthesis in these cells, whereas expression in axons suggests that some neurons can both synthesize and catabolize NAA.


Assuntos
Amidoidrolases/metabolismo , Sistema Nervoso Central/enzimologia , Animais , Astrócitos/enzimologia , Sistema Nervoso Central/anatomia & histologia , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Ratos , Tremor/enzimologia , Tremor/patologia
11.
J Neurol Sci ; 298(1-2): 91-5, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20804986

RESUMO

Huntington disease (HD) is a disorder characterized by chorea, dystonia, bradykinesia, cognitive decline and psychiatric comorbidities. Balance and gait impairments, as well as falls, are common manifestations of the disease. The importance of compensatory rapid stepping to maintain equilibrium in older adults is established, yet little is known of the role of stepping response times (SRTs) in balance control in people with HD. SRTs and commonly-used clinical measures of balance and mobility were evaluated in fourteen symptomatic participants with HD, and nine controls at a university mobility research laboratory. Relative and absolute reliability, as well as minimal detectable change in SRT were quantified in the HD participants. HD participants exhibited slower SRTs and poorer dynamic balance, mobility and motor performance than controls. HD participants also reported lower balance confidence than controls. Deficits in SRT were associated with low balance confidence and impairments on clinical measures of balance, mobility, and motor performance in HD participants. Measures of relative and absolute reliability indicate that SRT is reliable and reproducible across trials in people with HD. A moderately low percent minimal detectable change suggests that SRT appears sensitive to detecting real change in people with HD. SRT is impaired in people with HD and may be a valid and objective marker of disease progression.


Assuntos
Marcha/fisiologia , Doença de Huntington/fisiopatologia , Limitação da Mobilidade , Equilíbrio Postural/fisiologia , Tempo de Reação/fisiologia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Desempenho Psicomotor/fisiologia , Reprodutibilidade dos Testes
12.
Hum Mol Genet ; 19(14): 2767-79, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20430936

RESUMO

The spectrum of mutations (missense, non-sense and splice-site) associated with hereditary spastic paraplegia 4 (HSP-SPG4) (SPG4:OMIM#182601) has suggested that this autosomal dominant disease results from loss of function. Because the protein encoded by SPG4, termed spastin, is a microtubule-severing enzyme, a loss-of-function scenario for the disease suggests that corticospinal axons degenerate due to inadequate microtubule severing resulting from inactivation of one spastin allele. Lending more complexity to the situation, there are two major isoforms of spastin (M1 and M87) translated from two start codons. M87 is widely expressed, while M1 is appreciably detected only in adult spinal cord. Here, we focused on four HSP-associated mutations of the SPG4 gene located outside of the AAA region essential for microtubule severing. We found that none of these mutations affected the enzymatic activity or expression levels of either M1 or M87. Three of the mutations resulted in dominant-negative activity of M1. Surprisingly, the S44L mutation, which is asymptomatic when present heterozygously, conferred dominant-negative activity, while the E112K mutation, which is symptomatic when present heterozygously, did not. Clinical symptoms reported for patients carrying the dominant-negative mutations L195V or 46Stop are not more severe than those reported for patients carrying the non-dominant-negative E112K mutation. These results indicate that there are cases of HSP-SPG4 that cannot be explained by insufficient spastin microtubule-severing activity.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/fisiologia , Paraplegia Espástica Hereditária/genética , Adenosina Trifosfatases/metabolismo , Sequência de Bases , Células Cultivadas , Genes Dominantes/fisiologia , Humanos , Perda de Heterozigosidade/fisiologia , Microtúbulos/genética , Microtúbulos/metabolismo , Modelos Biológicos , Mutação/fisiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , Multimerização Proteica/genética , Espastina , Transfecção
13.
Brain ; 133(Pt 5): 1391-402, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20395263

RESUMO

We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures. Biochemical studies of tau demonstrated a preponderance of 4R tau isoforms. The phenotype was linked to Xq26.3, and further analysis identified an in-frame 9 base pair deletion in the solute carrier family 9, isoform A6 (SLC9A6 gene), which encodes sodium/hydrogen exchanger-6 localized to endosomal vesicles. Sodium/hydrogen exchanger-6 is thought to participate in the targeting of intracellular vesicles and may be involved in recycling synaptic vesicles. The striking tau deposition in our subjects reveals a probable interaction between sodium/proton exchangers and cytoskeletal elements involved in vesicular transport, and raises the possibility that abnormalities of vesicular targeting may play an important role in more common disorders such as Alzheimer's disease and autism spectrum disorders.


Assuntos
Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Mutação , Trocadores de Sódio-Hidrogênio/genética , Proteínas tau/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Deleção de Genes , Ligação Genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/psicologia , Masculino , Microscopia Eletrônica , Biologia Molecular/métodos , Neuroglia/metabolismo , Neurônios/metabolismo , Linhagem , Fenótipo , Isoformas de Proteínas/metabolismo , Índice de Gravidade de Doença , Proteínas tau/ultraestrutura
14.
Am J Hum Genet ; 86(3): 343-52, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20170900

RESUMO

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doença dos Neurônios Motores/genética , Mutação de Sentido Incorreto , Adenosina Trifosfatases/química , Adenosina Trifosfatases/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte de Cátions/química , Proteínas de Transporte de Cátions/metabolismo , Células Cultivadas , Pré-Escolar , Cobre/metabolismo , ATPases Transportadoras de Cobre , Primers do DNA/genética , Feminino , Estudos de Associação Genética , Teste de Complementação Genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Síndrome dos Cabelos Torcidos/genética , Síndrome dos Cabelos Torcidos/metabolismo , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Doença dos Neurônios Motores/metabolismo , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência de Aminoácidos , Síndrome , Adulto Jovem
15.
Acta Neuropathol ; 118(4): 531-9, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19562355

RESUMO

Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.


Assuntos
Encéfalo/patologia , Morte Celular/genética , Proteína Proteolipídica de Mielina/genética , Neurônios/patologia , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/patologia , Adulto , Fatores Etários , Cromossomos Humanos X , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Bainha de Mielina/genética , Bainha de Mielina/patologia , Neuroglia/patologia
16.
J Neurol Sci ; 279(1-2): 109-13, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19193385

RESUMO

OBJECTIVE: X-linked Charcot Marie Tooth disease (CMT1X) is a hereditary demyelinating neuropathy caused by mutations in the GJB1 gene encoding the gap junction protein connexin 32 (Cx32). Some GJB1 mutations have been reported to cause transient clinical CNS dysfunction. We report a boy with persistent CNS abnormalities possibly caused by CMT1X. METHODS: A five year old boy was evaluated by clinical, electrophysiological, MRI and genetic testing. RESULTS: The patient's early motor milestones were normal to age 5 months. His subsequent course was one of slow improvement punctuated by brief periods of loss of ability to sit between age 5 and 10 months, loss of language between 12 months and 2 years and 1 episode of non-clinically observed resolved left-sided facial weakness. At age 5, he had truncal instability, appendicular ataxia, and dysarthric speech. Cognition was normal. He had mild toe weakness and intrinsic muscle atrophy. MRI evaluation was abnormal. Electrophysiologic testing revealed slowed motor conduction velocities and sensory responses of low amplitude. Genetic workup was normal excepting a novel missense mutation in GJB1, causing a p.54N>H substitution. CONCLUSION: The patient has persistent CNS abnormalities characterized by dysarthria and ataxia. These are similar to transient CNS abnormalities reported in patients with CMT1X. These CNS findings may be the direct result of his novel Cx32 mutation.


Assuntos
Ataxia/fisiopatologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Disartria/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Adulto , Ataxia/genética , Encéfalo/patologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Pré-Escolar , Conexinas/genética , Análise Mutacional de DNA , Disartria/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Transtornos da Linguagem/genética , Transtornos da Linguagem/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mães , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Mutação de Sentido Incorreto , Condução Nervosa
17.
J Child Neurol ; 24(5): 618-24, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19151366

RESUMO

Pelizaeus-Merzbacher disease is a rare X-linked disorder caused by mutations of the proteolipid protein 1 gene that encodes a structural component of myelin. It is characterized by progressive psychomotor delay, nystagmus, spastic quadriplegia, and cerebellar ataxia. Variable clinical expression was seen in 5 members of a family bearing a novel missense mutation in proteolipid protein 1, c.619T>C. Symptomatic patients included a 6-year-old girl, her younger brother, and their maternal uncle, a 29-year-old college graduate initially diagnosed with cerebral palsy; their brain magnetic resonance imaging studies showed diffuse dysmyelination. The mother had a history of delayed walking, achieved independently by age 3; she and the maternal grandmother were asymptomatic on presentation. Review of clinical information and family history led to consideration of Pelizaeus-Merzbacher disease. Subsequent identification of the causal mutation enabled preimplantation genetic diagnosis and the birth of an unaffected child.


Assuntos
Mutação de Sentido Incorreto , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Adulto , Encéfalo/patologia , Paralisia Cerebral/diagnóstico , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bainha de Mielina/patologia , Linhagem , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/patologia , Mutação Puntual , Diagnóstico Pré-Implantação
18.
Eur J Neurosci ; 30(11): 2030-41, 2009 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-20128842

RESUMO

Highly purified oligodendroglial lineage cells from mice lacking functional bax and bak genes were resistant to apoptosis after in-vitro differentiation, indicating an essential role of the intrinsic apoptotic pathway in apoptosis of oligodendrocytes in the absence of neurons (axons) and other glial cells. These mice therefore provide a valuable tool with which to evaluate the significance of the intrinsic apoptotic pathway in regulating the population sizes of oligodendrocytes and oligodendroglial progenitor cells. Quantitative analysis of the optic nerves and the dorsal columns of the spinal cord revealed that the absolute numbers of mature oligodendrocytes immunolabeled for aspartoacylase and adult glial progenitor cells expressing NG2 chondroitin sulfate proteoglycan were increased in both white matter tracts of adult bax/bak-deficient mice and, to a lesser extent, bax-deficient mice, except that there was no increase in NG2-positive progenitor cells in the dorsal columns of these strains of mutant mice. These increases in mature oligodendrocytes and progenitor cells in bax/bak-deficient mice were unexpectedly proportional to increases in numbers of axons in these white matter tracts, thus retaining the oligodendroglial lineage to axon ratios of at most 1.3-fold of the physiological numbers. This is in contrast to the prominent expansion in numbers of neural precursor cells in the subventricular zones of these adult mutant mice. Our study indicates that homeostatic control of cell number is different for progenitors of the oligodendroglial and neuronal lineages. Furthermore, regulatory mechanism(s) operating in addition to apoptotic elimination through the intrinsic pathway, appear to prevent the overproduction of highly mitotic oligodendroglial progenitor cells.


Assuntos
Axônios/fisiologia , Oligodendroglia/fisiologia , Proteína Killer-Antagonista Homóloga a bcl-2/deficiência , Proteína X Associada a bcl-2/deficiência , Animais , Animais Recém-Nascidos , Antígenos/metabolismo , Apoptose/genética , Encéfalo/citologia , Morte Celular/genética , Diferenciação Celular/genética , Células Cultivadas , Gangliosídeos/metabolismo , Regulação da Expressão Gênica/genética , Marcação In Situ das Extremidades Cortadas/métodos , Camundongos , Camundongos Knockout , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Antígenos O/metabolismo , Nervo Óptico/citologia , Nervo Óptico/crescimento & desenvolvimento , Nervo Óptico/metabolismo , Proteoglicanas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , RNA Mensageiro/metabolismo , Células-Tronco/fisiologia , Fatores de Tempo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética
19.
J Neurosci Res ; 85(6): 1347-57, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17335073

RESUMO

Plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1 (NF1) and have a risk of malignant progression. Past efforts to establish xenograft models for neurofibroma involved the implantation of tumor fragments or heterogeneous primary cultures, which rarely achieved significant tumor growth. We report a practical and reproducible animal model of plexiform-like neurofibroma by xenograft of an immortal human NF1 tumor-derived Schwann cell line into the peripheral nerve of scid mice. The S100 and p75 positive sNF94.3 cell line was shown to possess a normal karyotype and have apparent full-length neurofibromin by Western blot. These cells were shown to have a constitutional NF1 microdeletion and elevated Ras-GTP activity, however, suggesting loss of normal neurofibromin function. Localized intraneural injection of the cell line sNF94.3 produced consistent and slow growing tumors that infiltrated and disrupted the host nerve. The xenograft tumors resembled plexiform neurofibromas with a low rate of proliferation, abundant extracellular matrix (hypocellularity), basal laminae, high vascularity, and mast cell infiltration. The histologic features of the developed tumors were particularly consistent with those of human plexiform neurofibroma as well. Intraneural xenograft of sNF94.3 cells enables the precise initiation of intraneural, plexiform-like tumors and provides a highly reproducible model for the study of plexiform neurofibroma tumorigenesis. This model facilitates testing of potential therapeutic interventions, including angiogenesis inhibitors, in a relevant cellular environment.


Assuntos
Linhagem Celular Tumoral , Neoplasias Pulmonares/patologia , Neurofibromatose 1/patologia , Células de Schwann/citologia , Adulto , Animais , Western Blotting , Feminino , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias/métodos , Proteínas do Tecido Nervoso/metabolismo , Neurofibromina 1/genética , Células de Schwann/enzimologia , Transplante Heterólogo/métodos , Proteínas ras/metabolismo
20.
FASEB J ; 20(12): 2139-41, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16935940

RESUMO

Mutations in the gene for aspartoacylase (ASPA), which catalyzes deacetylation of N-acetyl-L-aspartate in the central nervous system (CNS), result in Canavan Disease, a fatal dysmyelinating disease. Consistent with its role in supplying acetate for myelin lipid synthesis, ASPA is thought to be cytoplasmic. Here we describe the occurrence of ASPA within nuclei of rat brain and kidney, and in cultured rodent oligodendrocytes. Immunohistochemistry showed cytoplasmic and nuclear ASPA staining, the specificity of which was demonstrated by its absence from tissues of the Tremor rat, an ASPA-null mutant. Subcellular fractionation analysis revealed low enzyme activity against NAA in nuclear fractions from normal rats. Whereas two recent reports have indicated that ASPA exists as a dimer, size-exclusion chromatography of subcellular fractions showed ASPA is an active monomer in both subcellular fractions. Western blotting detected ASPA as a single 38 kD band. Because ASPA is small enough to passively diffuse into the nucleus, we constructed, expressed, and detected in COS-7 cells a green fluorescent protein-human ASPA (GFP-hASPA) fusion protein larger than the permissible size for the nuclear pore complex. GFP-hASPA was enzymatically active and showed mixed nuclear-cytoplasmic distribution. We conclude that ASPA is a regulated nuclear-cytoplasmic protein that may have distinct functional roles in the two cellular compartments.


Assuntos
Amidoidrolases/análise , Transporte Ativo do Núcleo Celular , Amidoidrolases/genética , Amidoidrolases/isolamento & purificação , Animais , Encéfalo/enzimologia , Fracionamento Celular , Núcleo Celular/enzimologia , Citoplasma/enzimologia , Proteínas de Fluorescência Verde/genética , Humanos , Rim/enzimologia , Ratos , Transfecção
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