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2.
Eur J Med Genet ; 63(2): 103729, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31319224

RESUMO

Non-ossifying fibromas are seen in different disorders recognizable by specific features. Indeed, osteoglophonic dysplasia (OD) is characterized by radiolucent bone lesions associated with severe short stature, dysmorphism and failure of dental eruption. This syndrome is caused by heterozygous activating mutations in the immunoglobulin-like D3 domain of the FGFR1 gene, encoding a tyrosine kinase. Here, we report three patients from the same family presenting with radiolucent bone lesions and teeth retentions. Exome sequencing allowed identification of a novel mutation c.917C > T, p. Pro306Leu in exon 7 of the FGFR1 gene. Our patients present with normal stature and no severe dysmorphism. This report describes a mild form of OD and expands the phenotype related to FGFR1 mutations. These findings emphasize the need to consider FGFR1 variants in the case of multiple non-ossifying bone lesions associated with dental eruption anomalies.


Assuntos
Osteocondrodisplasias/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Anormalidades Dentárias/genética , Criança , Éxons/genética , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/enzimologia , Linhagem , Fenótipo , Domínios Proteicos/genética , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/diagnóstico por imagem , Sequenciamento Completo do Exoma
3.
Eur J Med Genet ; 61(12): 755-758, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30121372

RESUMO

Autosomal recessive missense Rotatin (RTTN) mutations are responsible for syndromic forms of malformation of cortical development, ranging from isolated polymicrogyria to microcephaly associated with primordial dwarfism and other major malformations. We identified, by trio based whole exome sequencing, a homozygous missense mutation in the RTTN gene (c.2953A > G; p.(Arg985Gly)) in one Moroccan patient from a consanguineous family. The patient showed early onset primary microcephaly, detected in the fetal period, postnatal growth restriction, encephalopathy with hyperkinetic movement disorders and self-injurious behavior with sleep disturbance. Brain MRI showed an extensive dysgyria associated with nodular heterotopia, large interhemispheric arachnoid cyst and corpus callosum hypoplasia.


Assuntos
Proteínas de Transporte/genética , Nanismo/genética , Microcefalia/genética , Polimicrogiria/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Consanguinidade , Bases de Dados Genéticas , Nanismo/diagnóstico por imagem , Nanismo/patologia , Feminino , Homozigoto , Humanos , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Marrocos/epidemiologia , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Polimicrogiria/diagnóstico por imagem , Polimicrogiria/patologia
4.
Am J Med Genet A ; 176(5): 1091-1098, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29681083

RESUMO

Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Calcinose/diagnóstico , Calcinose/genética , Otopatias/diagnóstico , Otopatias/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Adolescente , Sequência de Aminoácidos , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Proteínas do Tecido Nervoso/química , Conformação de Ácido Nucleico , Linhagem , Fenótipo , Conformação Proteica , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Fatores de Transcrição/química
5.
Blood ; 131(14): 1545-1555, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29378696

RESUMO

Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow plasma cells (PCs) engaged in an immune response. Multiplex polymerase chain reaction at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone marrow PCs. This observation suggested that, in addition to a process of selection, a maturation induced on B-cell depletion drove PCs toward a long-lived program. We showed that B-cell activating factor (BAFF) and CD4+ T cells play a major role in the PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia.


Assuntos
Fator Ativador de Células B/imunologia , Linfócitos T CD4-Positivos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Depleção Linfocítica , Plasmócitos/imunologia , Baço/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Sobrevivência Celular , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Plasmócitos/patologia , Baço/patologia
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.
J Med Genet ; 54(5): 324-329, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28069933

RESUMO

BACKGROUND: While mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation and according to cell type, very little is known regarding the mechanism which accurately controls mtDNA copy number in human. Exon 2 of the human POLG gene, encoding the catalytic subunit of the mitochondrial-specific DNA polymerase gamma, contains a CpG island, highly conserved in mice and human. Changes of DNA methylation at the POLG locus have been shown to modulate mtDNA copy number during cell differentiation in both mouse and human. METHODS: We have investigated the epigenetic modification of the POLG gene, by assessing the methylation level of its exon 2 using deep-Next Generation Sequencing analysis of bisulfite-treated DNA. Analysis were performed on various tissues at either postnatal or prenatal stages, on samples from carriers of mtDNA mutations, patients carrying two loss-of-function POLG mutations and controls. RESULTS: Very high methylation levels at POLG exon 2 were found (94±3%) and no variation was observed according to either developmental stage or tissue of origin, except for sperm samples for which lower methylation levels were found (80%). This high level of methylation was neither correlated with the presence of mtDNA mutations (94±1% of methylated alleles), nor with biallelic POLG mutations (93%±2%), even in tissues where a mtDNA depletion had been observed. CONCLUSIONS: This study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified.


Assuntos
Diferenciação Celular/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Polimerase do DNA Mitocondrial/genética , DNA Mitocondrial/genética , Éxons/genética , Mutação/genética , Adolescente , Adulto , Animais , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Camundongos , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
8.
mBio ; 7(4)2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27486197

RESUMO

UNLABELLED: Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia, affecting infants and adults worldwide. N. meningitidis is also a common inhabitant of the human nasopharynx and, as such, is highly adapted to its niche. During bacteremia, N. meningitidis gains access to the blood compartment, where it adheres to endothelial cells of blood vessels and causes dramatic vascular damage. Colonization of the nasopharyngeal niche and communication with the different human cell types is a major issue of the N. meningitidis life cycle that is poorly understood. Here, highly saturated random transposon insertion libraries of N. meningitidis were engineered, and the fitness of mutations during routine growth and that of colonization of endothelial and epithelial cells in a flow device were assessed in a transposon insertion site sequencing (Tn-seq) analysis. This allowed the identification of genes essential for bacterial growth and genes specifically required for host cell colonization. In addition, after having identified the small noncoding RNAs (sRNAs) located in intergenic regions, the phenotypes associated with mutations in those sRNAs were defined. A total of 383 genes and 8 intergenic regions containing sRNA candidates were identified to be essential for growth, while 288 genes and 33 intergenic regions containing sRNA candidates were found to be specifically required for host cell colonization. IMPORTANCE: Meningococcal meningitis is a common cause of meningitis in infants and adults. Neisseria meningitidis (meningococcus) is also a commensal bacterium of the nasopharynx and is carried by 3 to 30% of healthy humans. Under some unknown circumstances, N. meningitidis is able to invade the bloodstream and cause either meningitis or a fatal septicemia known as purpura fulminans. The onset of symptoms is sudden, and death can follow within hours. Although many meningococcal virulence factors have been identified, the mechanisms that allow the bacterium to switch from the commensal to pathogen state remain unknown. Therefore, we used a Tn-seq strategy coupled to high-throughput DNA sequencing technologies to find genes for proteins used by N. meningitidis to specifically colonize epithelial cells and primary brain endothelial cells. We identified 383 genes and 8 intergenic regions containing sRNAs essential for growth and 288 genes and 33 intergenic regions containing sRNAs required specifically for host cell colonization.


Assuntos
Endocitose , Células Endoteliais/microbiologia , Células Epiteliais/microbiologia , Neisseria meningitidis/genética , Neisseria meningitidis/patogenicidade , Pequeno RNA não Traduzido/genética , Fatores de Virulência/genética , Linhagem Celular , Elementos de DNA Transponíveis , Técnicas de Inativação de Genes , Biblioteca Gênica , Humanos , Mutagênese Insercional , Neisseria meningitidis/crescimento & desenvolvimento
9.
Am J Hum Genet ; 98(5): 971-980, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27108797

RESUMO

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.


Assuntos
Aniridia/etiologia , Ataxia Cerebelar/etiologia , Genes Dominantes/genética , Genes Recessivos/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Deficiência Intelectual/etiologia , Mutação/genética , Adolescente , Aniridia/patologia , Ataxia Cerebelar/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/patologia , Masculino , Linhagem
10.
Am J Hum Genet ; 97(2): 311-8, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166481

RESUMO

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.


Assuntos
Proteínas de Ciclo Celular/genética , Transtornos da Motilidade Ciliar/genética , Códon sem Sentido/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Hidrocefalia/genética , Fenótipo , Síndrome de Costela Curta e Polidactilia/genética , Sequência de Bases , Transtornos da Motilidade Ciliar/patologia , Europa Oriental , Evolução Fatal , Efeito Fundador , Humanos , Funções Verossimilhança , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
11.
Am J Med Genet A ; 167A(8): 1908-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25846674

RESUMO

Intellectual disability is a neurodevelopmental disorder of impaired adaptive skills and low intelligence quotient. The overall prevalence is estimated at 2-3% in the general population with extreme clinical and genetic heterogeneity, and it has been associated with possibly causative mutations in more than 700 identified genes. In a recent review, among over 100 X-linked intellectual disability causative genes, eight were reported as "awaiting replication." Exome sequencing in a large family identified a missense mutation in RPL10 highly suggestive of X-linked intellectual disability. Herein, we report on the clinical description of four affected males. All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism. In the literature, two mutations were reported in three families with affected males presenting with autism. This report confirms the implication of RPL10 mutations in neurodevelopmental disorders and extends the associated clinical spectrum from autism to syndromic intellectual disability.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Proteínas Ribossômicas/genética , Feminino , Humanos , Masculino , Linhagem , Proteína Ribossômica L10
12.
Blood ; 122(23): 3713-22, 2013 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-24089328

RESUMO

Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 (n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus-negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor κB pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.


Assuntos
Subunidade alfa de Receptor de Interleucina-10/deficiência , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/deficiência , Subunidade beta de Receptor de Interleucina-10/genética , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Genes rel , Predisposição Genética para Doença , Centro Germinativo/imunologia , Centro Germinativo/patologia , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Interleucina-10/metabolismo , Linfoma de Células B/etiologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Mutação , NF-kappa B/metabolismo , Linhagem , Transdução de Sinais
13.
Am J Hum Genet ; 92(2): 265-70, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23312594

RESUMO

Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.


Assuntos
Aldeído Desidrogenase/genética , Anoftalmia/enzimologia , Anoftalmia/genética , Genes Recessivos/genética , Microftalmia/enzimologia , Microftalmia/genética , Mutação/genética , Aldeído Oxirredutases , Segregação de Cromossomos/genética , Éxons/genética , Feminino , Ligação Genética , Células HEK293 , Homozigoto , Humanos , Íntrons/genética , Masculino , Proteínas Mutantes/metabolismo , Linhagem , Análise de Sequência de DNA
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