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1.
Hum Mol Genet ; 33(12): 1055-1063, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38493358

RESUMO

Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models. Here, we report a de novo missense heterozygous variant in CLDN25 (c. 745G>C, p. A249P) found in a patient diagnosed with Pelizaeus-Merzbacher-like leukodystrophy and presenting with symptoms such as delayed motor development, several episodes of tonic absent seizures and generalized dystonia. The variant protein does not localize to the cell-cell borders where it would normally be expected to be expressed. Amino acid position 249 is located 4 amino acids from the C-terminal end of the protein where most claudin family members have a conserved binding motif for the key scaffolding protein ZO-1. However, CLDN-25 does not contain this motif. Here, we show that the C-terminal end of CLDN-25 is required for its junctional localization in a ZO-1 independent manner. The A249P mutant protein as well as a deletion mutant lacking its last 5 C-terminal amino acids also failed to localize to the cell-cell border in vitro. Intriguingly, cellular knockout of CLDN25, in vitro, appeared to increase the integrity of the tight junction between 2 contacting cells, while driving highly unusual increased movement of solutes between cells. We propose that the barrier function of CLDN-25 is akin to a decoy claudin, whereby decreasing its expression in "leaky" epithelial cells and endothelial cells will drive dynamic changes in the adhesion and interaction capacity of cell-cell contact points. While it remains unclear how this de novo CLDN-25 mutant induces leukodystrophy, our findings strongly suggest that this mutation induces haploinsufficiency of CLDN-25. Elucidating the function of this uncharacterized claudin protein will lead to a better understanding of the role of claudin proteins in health and disease.


Assuntos
Claudinas , Doença de Pelizaeus-Merzbacher , Humanos , Claudinas/genética , Claudinas/metabolismo , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/metabolismo , Mutação com Perda de Função , Masculino , Mutação de Sentido Incorreto , Feminino , Animais , Sequência de Aminoácidos
2.
J Med Genet ; 59(2): 204-208, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33199448

RESUMO

BACKGROUND: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs. OBJECTIVE AND METHODS: To document neuroimaging data in six patients with PNPT1 highlighting novel findings. RESULTS: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection. CONCLUSION: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.


Assuntos
Encéfalo/diagnóstico por imagem , Exorribonucleases/genética , Doença de Leigh/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Adulto , Encéfalo/patologia , Criança , Pré-Escolar , Humanos , Interferon Tipo I/genética , Doença de Leigh/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Doenças Mitocondriais/diagnóstico por imagem , Neuroimagem , Sequenciamento Completo do Genoma
3.
Ann Neurol ; 90(1): 143-158, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33999436

RESUMO

OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021;90:149-164.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Hipopituitarismo/genética , Alelos , Encefalopatias/patologia , Pré-Escolar , Epilepsia/patologia , Feminino , Humanos , Hipopituitarismo/patologia , Lactente , Masculino , Hipófise/patologia , Sequenciamento do Exoma , Adulto Jovem
5.
Brain ; 143(10): 2911-2928, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33103737

RESUMO

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.


Assuntos
Cílios/genética , Complexo de Golgi/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas de Transporte Vesicular/genética , Animais , Células Cultivadas , Cílios/patologia , Feminino , Complexo de Golgi/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/diagnóstico por imagem
6.
J Med Genet ; 57(2): 138-144, 2020 02.
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.


Assuntos
Transtorno Autístico/genética , Proteínas de Membrana/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Animais , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Pré-Escolar , Modelos Animais de Doenças , Drosophila melanogaster/genética , Exoma/genética , Predisposição Genética para Doença , Genótipo , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/patologia , Convulsões/patologia , Sequenciamento do Exoma
7.
Am J Hum Genet ; 100(4): 592-604, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28285769

RESUMO

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.


Assuntos
Anormalidades Múltiplas/genética , Ciclofilinas/genética , Mutação , Peptidilprolil Isomerase/genética , Degeneração Retiniana/genética , Adolescente , Animais , Criança , Pré-Escolar , Ciclofilinas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Linhagem , Peptidilprolil Isomerase/metabolismo , Adulto Jovem
8.
Am J Hum Genet ; 101(6): 995-1005, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198722

RESUMO

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.


Assuntos
Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos Neurocognitivos/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/embriologia , Códon sem Sentido/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deformidades Congênitas dos Membros/genética , Disostose Mandibulofacial/genética , Sistema Nervoso Periférico/anormalidades , Sistema Nervoso Periférico/enzimologia
9.
Epilepsia ; 61(11): 2461-2473, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32954514

RESUMO

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.


Assuntos
Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Variação Genética/genética , Canais de Potássio Shab/genética , Adolescente , Adulto , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/tendências , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Eur J Pediatr ; 179(4): 579-586, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31848748

RESUMO

Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants with growing evidence that genetic factors contribute largely to moderate and severe cases. We assessed by exome sequencing if rare genetic variants could account for extremely severe phenotypes. We selected 6 infants born very preterm with severe bronchopulmonary dysplasia and 8 very preterm born controls for exome sequencing. We filtered whole exome sequencing results to include only rare variants and selected variants and/or genes with variants that were present in at least 2 cases and absent in controls. We selected variants, all heterozygous, in 9 candidate genes, 7 with a putative role in lung development and 2 that displayed 3 variations in 3 different cases, independently of their potential role in lung development. Sequencing of 5 other severe cases for these variants did not replicate our results.Conclusion: In selected preterm born infants with severe bronchopulmonary dysplasia and controls, we failed to find any rare variant shared by several infants with an extremely severe phenotype. Our results are not consistent with the role of rare causative variants in bronchopulmonary dysplasia's development and argue for the highly polygenic nature of susceptibility of this disorder.What is Known:• Bronchopulmonary dysplasia is a multifactorial disease resulting from complex environmental and genetic interactions occurring in an immature lung.• It is not known whether rare genetic variants in coding regions could account for extreme phenotypes of the disease.What is New:• In a group of infants with an extreme phenotype of bronchopulmonary dysplasia and in comparison to controls, no common genetic variants were found, nor did variants that were select in other exome studies in this setting.• These results argue for the highly polygenic nature of susceptibility of bronchopulmonary dysplasia.


Assuntos
Displasia Broncopulmonar/genética , Sequenciamento do Exoma/métodos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Idade Gestacional , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Lactente Extremamente Prematuro , Recém-Nascido , Masculino , Fenótipo , Estudos Prospectivos
11.
Hum Mol Genet ; 26(3): 599-610, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28025328

RESUMO

Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.


Assuntos
Proteínas de Ciclo Celular/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Disgenesia da Tireoide/genética , Proteínas de Ciclo Celular/biossíntese , Movimento Celular/genética , Exoma/genética , Feminino , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mitose/genética , Linhagem , Disgenesia da Tireoide/patologia
13.
Genet Med ; 21(4): 837-849, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30206421

RESUMO

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.


Assuntos
Encefalopatias/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Convulsões/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encefalopatias/epidemiologia , Encefalopatias/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Linhagem , Fenótipo , Isoformas de Proteínas/genética , Convulsões/epidemiologia , Convulsões/fisiopatologia , Caracteres Sexuais
14.
J Med Genet ; 55(6): 378-383, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29358270

RESUMO

BACKGROUND: Because the mitochondrial respiratory chain (RC) is ubiquitous, its deficiency can theoretically give rise to any symptom in any organ or tissue at any age with any mode of inheritance, owing to the twofold genetic origin of respiratory enzyme machinery, that is, nuclear and mitochondrial. Not all respiratory enzyme deficiencies are primary and secondary or artefactual deficiency is frequently observed, leading to a number of misleading conclusions and inappropriate investigations in clinical practice. This study is aimed at investigating the potential role of brain MRI in distinguishing primary RC deficiency from phenocopies and other aetiologies. METHODS: Starting from a large series of 189 patients (median age: 3.5 years (8 days-56 years), 58% males) showing signs of RC enzyme deficiency, for whom both brain MRIs and disease-causing mutations were available, we retrospectively studied the positive predictive value (PPV) and the positive likelihood ratio (LR+) of brain MRI imaging and its ability to discriminate between two groups: primary deficiency of the mitochondrial RC machinery and phenocopies. RESULTS: Detection of (1) brainstem hyperintensity with basal ganglia involvement (P≤0.001) and (2) lactate peak with either brainstem or basal ganglia hyperintensity was highly suggestive of primary RC deficiency (P≤0.01). Fourteen items had a PPV>95% and LR+ was greater than 9 for seven signs. Biallelic SLC19A3 mutations represented the main differential diagnosis. Non-significant differences between the two groups were found for cortical/subcortical atrophy, leucoencephalopathy and involvement of caudate nuclei, spinothalamic tract and corpus callosum. CONCLUSION: Based on these results and owing to invasiveness of skeletal muscle biopsies and cost of high-throughput DNA sequencing, we suggest giving consideration to brain MRI imaging as a diagnostic marker and an informative investigation to be performed in patients showing signs of RC enzyme deficiency.


Assuntos
Atrofia/diagnóstico , Encéfalo/diagnóstico por imagem , Diagnóstico Diferencial , Doenças Mitocondriais/diagnóstico , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/patologia , Valor Preditivo dos Testes , Adulto Jovem
15.
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.


Assuntos
Hipertensão Portal/genética , Mutação , Veia Porta/patologia , Proteínas/genética , Doenças Vasculares/genética , Adulto , Criança , Pré-Escolar , Constrição Patológica , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/patologia , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Doenças Vasculares/diagnóstico , Doenças Vasculares/patologia , Adulto Jovem
16.
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 do Exoma/métodos
17.
Neurogenetics ; 18(1): 23-28, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27726050

RESUMO

Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.


Assuntos
Transtornos Cognitivos/genética , Distonia/genética , Mosaicismo , Mutação de Sentido Incorreto , Convulsões/genética , ATPase Trocadora de Sódio-Potássio/genética , Transtorno Autístico/complicações , Transtorno Autístico/genética , Transtorno Autístico/patologia , Criança , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Distonia/complicações , Distonia/patologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Fenótipo , Recidiva , Convulsões/complicações , Convulsões/patologia , Irmãos , Estrabismo/complicações , Estrabismo/genética , Estrabismo/patologia
19.
J Med Genet ; 51(12): 834-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25351951

RESUMO

BACKGROUND: Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. METHODS: We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families. RESULTS: We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity. CONCLUSIONS: Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.


Assuntos
Aconitato Hidratase/genética , Mutação , Doenças do Nervo Óptico/genética , Aconitato Hidratase/metabolismo , Adulto , Encéfalo/patologia , Pré-Escolar , Ciclo do Ácido Cítrico , Ativação Enzimática , Exoma , Evolução Fatal , Feminino , Expressão Gênica , Genes Recessivos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento por Ressonância Magnética , Masculino , Oftalmoscópios , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/metabolismo , Avaliação de Resultados da Assistência ao Paciente , Irmãos
20.
Eur J Med Genet ; 72: 104979, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39423951

RESUMO

Biallelic pathogenic variants in CNTNAP2, a gene encoding the contactin-associated protein-like 2, have been reported in patients with various clinical presentations including intellectual disability (ID), autistic spectrum disorders (ASD), psychiatric disorders, and focal epilepsy rarely associated to focal cortical dysplasia. We report four children carrying novel biallelic CNTNAP2 pathogenic variants. They present global developmental delay, psychiatric disorders, and focal epilepsy. All patients displayed brain MRI abnormalities consistent with focal temporal dysplasia. One patient had a temporal resection before the availability of genetic testing. Focal cortical dysplasia represents a frequent finding related to focal refractory epilepsy in CNTNAP2 affected patients, and surgery seems to be ineffective in this setting. The genetic testing could therefore be impactful on treatment choices in refractory focal epilepsies.

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