Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 53
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Genet ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439720

RESUMO

BACKGROUND: Autistic spectrum disorders (ASDs) with developmental delay and seizures are a genetically heterogeneous group of diseases caused by at least 700 different genes. Still, a number of cases remain genetically undiagnosed. OBJECTIVE: The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented a similar clinical phenotype that included an ASD, intellectual disability (ID) and seizures. METHODS: Whole-exome sequencing was used to identify pathogenic variants in the two individuals. Functional studies performed in the Drosophila melanogaster model was used to assess the protein function in vivo. RESULTS: Probands shared a heterozygous de novo secretory carrier membrane protein (SCAMP5) variant (NM_001178111.1:c.538G>T) resulting in a p.Gly180Trp missense variant. SCAMP5 belongs to a family of tetraspanin membrane proteins found in secretory and endocytic compartments of neuronal synapses. In the fly SCAMP orthologue, the p.Gly302Trp genotype corresponds to human p.Gly180Trp. Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect. CONCLUSION: Our study identifies SCAMP5 deficiency as a cause for ASD and ID and underscores the importance of synaptic vesicular trafficking in neurodevelopmental disorders.

2.
Psychiatr Genet ; 29(4): 103-110, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30933048

RESUMO

BACKGROUND: Anorexia nervosa is a complex neuropsychiatric disorder presenting with life-threatening low body weight, and a persistent fear of gaining weight. To date, no whole exome sequencing was performed in male individuals with anorexia nervosa. AIM AND METHODS: Here, we performed an exome analysis in two independent families with male individuals with anorexia nervosa and found variants in the Neuronatin (NNAT) gene in both probands. To confirm our data, we carried out the screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa. RESULTS: Exome sequencing revealed a nonsense variant p.Trp33* in NNAT in one patient and a rare variant in the 5'UTR region of NNAT in the other patient. Screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa allowed to identify 11 other NNAT variants showing that 40.00% and 6.25% of male and female anorexia nervosa individuals carried a NNAT variant, respectively. Moreover, two novel missense variants were identified in female anorexia nervosa patients. CONCLUSION: Our data suggest that NNAT variants and NNAT expression changes may be associated with susceptibility to eating disorders such as anorexia nervosa.

4.
Gene ; 679: 305-313, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30217758

RESUMO

Histone lysine methylation influences processes such as gene expression and DNA repair. Thirty Jumonji C (JmjC) domain-containing proteins have been identified and phylogenetically clustered into seven subfamilies. Most JmjC domain-containing proteins have been shown to possess histone demethylase activity toward specific histone methylation marks. One of these subfamilies, the KDM5 family, is characterized by five conserved domains and includes four members. Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals. Here, we report two novel de novo splice variants in the KDM5B gene in three patients with ID and ASD. The c.808 + 1G > A variant was identified in a boy with mild ID and autism traits and is associated with a significant reduced KDM5B mRNA expression without alteration of its H3K4me3 pattern. In contrast, the c.576 + 2T > C variant was found in twins with global delay in developmental milestones, poor language and ASD. This variant causes the production of an abnormal transcript which may produce an altered protein with the loss of the ARID1B domain with an increase in global gene H3K4me3. Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder. However, some variants may also cause gain of function, and need to be interpreted with caution, and functional studies should be performed to identify the molecular consequences of these different rare variants.


Assuntos
Processamento Alternativo , Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Transtorno do Espectro Autista/metabolismo , Linhagem Celular , Criança , Deficiências do Desenvolvimento/metabolismo , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Humanos , Deficiência Intelectual/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Masculino , Proteínas Nucleares/metabolismo , Linhagem , Proteínas Repressoras/metabolismo
5.
Liver Int ; 38(2): 358-364, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28792652

RESUMO

BACKGROUND & AIMS: Obliterative portal venopathy (OPV) is characterized by lesions of portal vein intrahepatic branches and is thought to be responsible for many cases of portal hypertension in the absence of cirrhosis or obstruction of large portal or hepatic veins. In most cases the cause of OPV remains unknown. The aim was to identify a candidate gene of OPV. METHODS: Whole exome sequencing was performed in two families, including 6 patients with OPV. Identified mutations were confirmed by Sanger sequencing and expression of candidate gene transcript was studied by real time qPCR in human tissues. RESULTS: In both families, no mutations were identified in genes previously reported to be associated with OPV. In each family, we identified a heterozygous mutation (c.1783G>A, p.Gly595Arg and c.4895C>T, p.Thr1632Ile) in a novel gene located on chromosome 4, that we called FOPV (Familial Obliterative Portal Venopathy), and having a cDNA coding for 1793 amino acids. The FOPV mutations segregated with the disease in families and the pattern of inheritance was suggestive of autosomal dominant inherited OPV, with incomplete penetrance and variable expressivity. In silico analysis predicted a deleterious effect of each mutant and mutations concerned highly conserved amino acids in mammals. A deleterious heterozygous FOPV missense mutation (c.4244T>C, p.Phe1415Ser) was also identified in a patient with non-familial OPV. Expression study in liver veins showed that FOPV transcript was mainly expressed in intrahepatic portal vein. CONCLUSIONS: This report suggests that FOPV mutations may have a pathogenic role in some cases of familial and non-familial OPV.

6.
Brain ; 140(10): 2597-2609, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28969387

RESUMO

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.


Assuntos
Fibroblastos/citologia , Microcefalia/genética , Microcefalia/patologia , Mitose/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Células Cultivadas , Pré-Escolar , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Humanos , Antígeno Ki-67/metabolismo , Masculino , Microcefalia/diagnóstico por imagem , Células-Tronco Neurais/patologia , Interferência de RNA/fisiologia , Adulto Jovem
7.
Hum Mutat ; 38(8): 932-941, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28585349

RESUMO

De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the ß subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the ß subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.


Assuntos
Caseína Quinase II/genética , Deficiências do Desenvolvimento/genética , Epilepsias Mioclônicas/genética , Deficiência Intelectual/genética , Caseína Quinase II/metabolismo , Pré-Escolar , Hibridização Genômica Comparativa , Exoma/genética , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Sequenciamento Completo do Exoma/métodos
8.
J Neuropathol Exp Neurol ; 76(3): 195-205, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395088

RESUMO

Dyneins play a critical role in a wide variety of cellular functions such as the movement of organelles and numerous aspects of mitosis, making it central player in neocortical neurogenesis and migration. Recently, cytoplasmic dynein-1, heavy chain-1 (DYNC1H1) mutations have been found to cause a wide spectrum of brain cortical malformations. We report on the detailed neuropathological features of brain lesions from 2 fetuses aged 36 and 22 weeks of gestation (WG), respectively, carrying de novo DYNC1H1 mutations, p.Arg2720Lys and p.Val3951Ala and presenting the most severe phenotype reported to date. Analysis using the Dictyostelium discoideum dynein motor crystal structure showed that the mutations are both predicted to have deleterious consequences on the function of the motor domain. Both fetuses showed a similar macroscopic and histological brain malformative complex associating bilateral fronto-parietal polymicrogyria (PMG), dysgenesis of the corpus callosum and of the cortico-spinal tracts, along with brainstem and cerebellar abnormalities. Both exhibited extremely severe disrupted cortical lamination. Immunohistochemical studies provided the evidence for defects in cell proliferation and postmitotic neuroblast ability to exit from the subventricular zone resulting in a failure of radial migration toward the cortical plate, thus providing new insights for the understanding of the pathophysiology in these cortical malformations.


Assuntos
Encéfalo/anormalidades , Encéfalo/patologia , Dineínas do Citoplasma/genética , Mutação/genética , Fenótipo , Adulto , Técnicas de Cultura de Células , Feminino , Feto , Humanos , Neuropatologia , Gravidez , Estrutura Secundária de Proteína
9.
Eur J Hum Genet ; 25(5): 560-564, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28145425

RESUMO

p.(Arg320His) mutation in the KCNC1 gene in human 11p15.1 has recently been identified in patients with progressive myoclonus epilepsies, a group of rare inherited disorders manifesting with action myoclonus, myoclonic epilepsy, and ataxia. This KCNC1 variant causes a dominant-negative effect. Here we describe three patients from the same family with intellectual disability and dysmorphic features. The three affected individuals carry a c.1015C>T (p.(Arg339*)) nonsense variant in KCNC1 gene. As previously observed in the mutant mouse carrying a disrupted KCNC1 gene, these findings reveal that individuals with a KCNC1 loss-of-function variant can present intellectual disability without seizure and epilepsy.


Assuntos
Códon sem Sentido , Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Convulsões/genética , Canais de Potássio Shaw/genética , Adulto , Criança , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Linhagem , Convulsões/diagnóstico , Síndrome
10.
Nat Genet ; 48(11): 1349-1358, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27694961

RESUMO

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Mutação de Sentido Incorreto , Heterotopia Nodular Periventricular/genética , Ubiquitina-Proteína Ligases/genética , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Ubiquitina-Proteína Ligases Nedd4 , Domínios Proteicos/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina/metabolismo
12.
Eur J Med Genet ; 59(4): 249-56, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26732629

RESUMO

Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly.


Assuntos
Artrogripose/genética , Malformações do Desenvolvimento Cortical/genética , Microcefalia/genética , Tubulina (Proteína)/genética , Adulto , Artrogripose/fisiopatologia , Cerebelo/fisiopatologia , Feminino , Feto , Humanos , Malformações do Desenvolvimento Cortical/fisiopatologia , Microcefalia/fisiopatologia , Neurônios Motores/patologia , Mutação , Medula Espinal/fisiopatologia , Tubulina (Proteína)/deficiência
13.
Eur J Hum Genet ; 24(4): 611-4, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26395554

RESUMO

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.


Assuntos
Mutação em Linhagem Germinativa , Malformações do Desenvolvimento Cortical/genética , Mosaicismo , Adulto , Exoma , Feminino , Loci Gênicos , Humanos , Masculino , Linhagem , Proteínas Qa-SNARE/genética
14.
Eur J Med Genet ; 58(8): 416-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26188271

RESUMO

Heterozygous ACTG1 mutations are responsible for Baraitser-Winter cerebrofrontofacial syndrome which cortical malformation is characterized by pachygyria with frontal to occipital gradient of severity. We identified by whole exome sequencing in a cohort of 12 patients with prenatally diagnosed microlissencephaly, 2 foetal cases with missense mutations in the ACTG1 gene and in one case of living patient with typical Baraitser-Winter syndrome. Both foetuses and child exhibited microcephaly and facial dysmorphism consisting of microretrognatism, hypertelorism and low-set ears. Brain malformations included lissencephaly with an immature cortical plate, dysmorphic (2/3) or absent corpus callosum and vermian hypoplasia (2/3). Our results highlight the powerful diagnostic value of exome sequencing for patients with microlissencephaly, that may expand the malformation spectrum of ACTG1-related Baraitser-Winter cerebrofrontofacial syndrome and may suggest that ACTG1 could be added to the list of genes for assessing microlissencephaly.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Anormalidades Craniofaciais/genética , Microcefalia/genética , Mutação de Sentido Incorreto , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Aborto Eugênico , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Criança , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/patologia , Exoma , Éxons , Feminino , Feto , Expressão Gênica , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Masculino , Microcefalia/diagnóstico , Microcefalia/patologia
15.
Hum Mol Genet ; 24(4): 1106-18, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25305082

RESUMO

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.


Assuntos
Deficiência Intelectual/genética , Proteína Acessória do Receptor de Interleucina-1/genética , Mutação , Neurogênese/genética , Sinapses/genética , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Deficiência Intelectual/metabolismo , Proteína Acessória do Receptor de Interleucina-1/química , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Íntrons , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Deleção de Sequência , Transdução de Sinais , Sinapses/metabolismo
16.
Hum Mutat ; 36(1): 106-17, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25385192

RESUMO

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.


Assuntos
Encéfalo/patologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Malformações do Desenvolvimento Cortical/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Estudos de Associação Genética , Células HEK293 , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/metabolismo , Malformações do Desenvolvimento Cortical/patologia , Retardo Mental Ligado ao Cromossomo X/metabolismo , Retardo Mental Ligado ao Cromossomo X/patologia , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA , Adulto Jovem
17.
Acta Neuropathol Commun ; 2: 69, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-25059107

RESUMO

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).


Assuntos
Encéfalo/anormalidades , Encéfalo/patologia , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico , Malformações do Desenvolvimento Cortical do Grupo I/genética , Mutação/genética , Tubulina (Proteína)/genética , Autopsia , Encéfalo/metabolismo , Análise Mutacional de DNA , Feminino , Feto , Humanos , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/classificação
18.
Nat Neurosci ; 17(7): 923-33, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24859200

RESUMO

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.


Assuntos
Coristoma/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/fisiologia , Mutação/fisiologia , Células-Tronco Neurais/fisiologia , Sequência de Aminoácidos , Animais , Bromodesoxiuridina , Ciclo Celular/fisiologia , Movimento Celular/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Eletroporação , Humanos , Imuno-Histoquímica , Malformações Arteriovenosas Intracranianas/patologia , Íntrons/genética , Camundongos , Microscopia Confocal , Microtúbulos/fisiologia , Mitose/fisiologia , Dados de Sequência Molecular , Retroelementos/fisiologia , Fuso Acromático/fisiologia
19.
Brain ; 137(Pt 6): 1676-700, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24860126

RESUMO

Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.


Assuntos
Agenesia do Corpo Caloso/diagnóstico , Lisencefalia/diagnóstico , Malformações do Desenvolvimento Cortical/diagnóstico , Microcefalia/diagnóstico , Mutação/genética , Tubulina (Proteína)/genética , Adolescente , Adulto , Agenesia do Corpo Caloso/epidemiologia , Agenesia do Corpo Caloso/genética , Cerebelo/anormalidades , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Lisencefalia/epidemiologia , Masculino , Malformações do Desenvolvimento Cortical/epidemiologia , Microcefalia/epidemiologia , Microcefalia/genética , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/epidemiologia , Malformações do Sistema Nervoso/genética , Fenótipo , Adulto Jovem
20.
Neurology ; 82(12): 1068-75, 2014 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-24598713

RESUMO

OBJECTIVE: The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region. METHODS: We used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains. RESULTS: A homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4-deficient mice. Histologic examination of Fig4-null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations. CONCLUSIONS: This study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varón syndrome.


Assuntos
Cromossomos Humanos Par 6 , Epilepsia/genética , Flavoproteínas/genética , Malformações do Desenvolvimento Cortical/genética , Adulto , Animais , Células Cultivadas , Consanguinidade , Epilepsia/patologia , Epilepsia/fisiopatologia , Exoma , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Camundongos , Camundongos Knockout , Marrocos , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Fosfatases de Fosfoinositídeos , Monoéster Fosfórico Hidrolases
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA