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1.
Hum Mol Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600779

RESUMO

We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier's and patient's skin fibroblasts to approximately 50% and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E.coli was reduced to approximately 25% of the wild type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria, the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.

2.
Blood ; 134(1): 9-21, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-30940614

RESUMO

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

3.
Cell Discov ; 4: 61, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455981

RESUMO

A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status.

4.
EMBO Mol Med ; 10(4)2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29567797

RESUMO

Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

5.
Clin Immunol ; 168: 88-93, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27057999

RESUMO

LRBA (lipopolysaccharide-responsive and beige-like anchor protein) deficiency associates immune deficiency, lymphoproliferation, and various organ-specific autoimmunity. To date, prevalent symptoms are autoimmune cytopenias and enteropathy, and lymphocytic interstitial lung disease. In 2 siblings from a consanguineous family presenting with early onset polyautoimmunity, we presumed autosomal recessive inheritance and performed whole exome sequencing. We herein report the first case of early-onset, severe, chronic polyarthritis associated with LRBA deficiency. A novel 1bp insertion in the LRBA gene, abolishing protein expression, was identified in this family. Among the 2 brothers homozygous for LRBA mutation, one developed Evans syndrome and deceased at age 8.5 from complications of severe autoimmune thrombocytopenia. His brother, who carried the same homozygous LRBA mutation, early-onset erosive polyarthritis associated with chronic, bilateral, anterior uveitis and early onset type 1 diabetes mellitus. This report widens the clinical spectrum of LRBA deficiency and, in lights of the variable phenotypes described so far, prompts us to screen for this disease in patients with multiple autoimmune symptoms in the family, including severe, erosive, polyarticular juvenile arthritis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite/genética , Autoimunidade/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Artrite/complicações , Artrite/metabolismo , Pré-Escolar , Doença Crônica , Consanguinidade , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Exoma/genética , Saúde da Família , Evolução Fatal , Feminino , Humanos , Immunoblotting , Masculino , Linhagem , Análise de Sequência de DNA , Irmãos , Uveíte Anterior/complicações , Uveíte Anterior/genética , Uveíte Anterior/metabolismo
6.
Nat Commun ; 6: 8666, 2015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26487268

RESUMO

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.


Assuntos
Proteínas de Transporte/genética , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Mutação , Degeneração Retiniana/genética , Proteínas de Peixe-Zebra/genética , Animais , Western Blotting , Proteínas de Transporte/metabolismo , Polaridade Celular/genética , Dicroísmo Circular , Embrião não Mamífero , Feminino , Imunofluorescência , Técnicas de Inativação de Genes , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoprecipitação , Doenças Renais Císticas/metabolismo , Masculino , Microftalmia/genética , Linhagem , Degeneração Retiniana/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
7.
Am J Hum Genet ; 94(2): 288-94, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24439109

RESUMO

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.


Assuntos
Anormalidades Congênitas/genética , Genes Recessivos , Cadeias alfa de Integrinas/genética , Nefropatias/congênito , Rim/anormalidades , Anormalidades Urogenitais/genética , Anormalidades Congênitas/patologia , Feminino , Feto/anormalidades , Homozigoto , Humanos , Cadeias alfa de Integrinas/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Masculino , Mutação , Linhagem , Anormalidades Urogenitais/patologia
9.
Science ; 333(6046): 1161-3, 2011 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-21868677

RESUMO

MED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.


Assuntos
Regulação da Expressão Gênica , Genes Precoces , Deficiência Intelectual/genética , Complexo Mediador/genética , Mutação de Sentido Incorreto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Células Cultivadas , Imunoprecipitação da Cromatina , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Genes fos , Genes jun , Histonas/metabolismo , Humanos , Masculino , Linhagem , Regiões Promotoras Genéticas , Fator de Transcrição 4 , Fatores de Transcrição/metabolismo , Ativação Transcricional , Proteínas Elk-1 do Domínio ets/metabolismo
10.
J Clin Invest ; 121(1): 106-12, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21183795

RESUMO

Autoimmune diseases develop in approximately 5% of humans. They can arise when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in lymphocyte activation, survival, or death. For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects in self-tolerance checkpoints as a consequence of mutations in the death receptor-encoding gene TNF receptor superfamily, member 6 (TNFRSF6; also known as FAS). However, some mutation carriers remain asymptomatic throughout life. We have now demonstrated in 7 ALPS patients that the disease develops as a consequence of an inherited TNFRSF6 heterozygous mutation combined with a somatic genetic event in the second TNFRSF6 allele. Analysis of the patients' CD4(-)CD8(-) (double negative) T cells--accumulation of which is a hallmark of ALPS--revealed that in these cells, 3 patients had somatic mutations in their second TNFRSF6 allele, while 4 patients had loss of heterozygosity by telomeric uniparental disomy of chromosome 10. This observation provides the molecular bases of a nonmalignant autoimmune disease development in humans and may shed light on the mechanism underlying the occurrence of other autoimmune diseases.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Mutação , Receptor fas/genética , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/imunologia , Cromossomos Humanos Par 10/genética , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Perda de Heterozigosidade , Linfócitos Nulos/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Linhagem , Dissomia Uniparental , Adulto Jovem
11.
Eur J Hum Genet ; 12(6): 483-8, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15054395

RESUMO

Chronic distal spinal muscular atrophy (Chronic DSMA, MIM (*)607088) is a rare autosomal recessive disorder characterized by a progressive motor weakness and muscular atrophy, predominating in the distal parts of the limbs. A form of Chronic DSMA gene has been previously mapped to chromosome 11q13 in the 10.3 cM interval defined by loci D11S1889 and D11S1321. By linkage analysis in 12 European Chronic DSMA families, we showed that a disease gene maps to chromosome 11q13.3 (Z(max)=6.66 at theta=0.00 at the DSM4 locus) and suggested that this condition is genetically homogeneous. Recombination events allowed us to reduce the genetic interval to a 2.6 cM region, telomeric to the IGHMBP2 gene, excluding this gene as the disease causing gene in Chronic DSMA. Moreover, partial linkage disequilibrium was found between three rare alleles at loci D11S1369, DSM4 and D11S4184 and the mutant chromosome in European patients. Analysis of the markers at these loci strongly suggests that most Chronic DSMA chromosomes are derived from a single ancestor. Refinement of the Chronic DSMA locus will hopefully allow to test candidate genes and lead to identification of the disease-causing mutations.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Genes Recessivos , Desequilíbrio de Ligação , Atrofia Muscular Espinal/genética , Doença Crônica , Europa (Continente) , Família , Feminino , Efeito Fundador , Marcadores Genéticos , Humanos , Masculino , Repetições de Microssatélites/genética , Linhagem , Recombinação Genética
12.
Ann Neurol ; 51(5): 585-92, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12112104

RESUMO

Distal spinal muscular atrophy is a heterogeneous group of neuromuscular disorders caused by progressive anterior horn cell degeneration and characterized by progressive motor weakness and muscular atrophy, predominantly in the distal parts of the limbs. Here we report on chronic autosomal recessive distal spinal muscular atrophy in a large, inbred family with onset at various ages. Because this condition had some of the same clinical features as spinal muscular atrophy with respiratory distress, we tested the disease gene for linkage to chromosome 11q and mapped the disease locus to chromosome 11q13 in the genetic interval that included the spinal muscular atrophy with respiratory distress gene (D11S1889-D11S1321, Z(max) = 4.59 at theta = 0 at locus D11S4136). The sequencing of IGHMBP2, the human homologue of the mouse neuromuscular degeneration gene (nmd) that accounts for spinal muscular atrophy with respiratory distress, failed to detect any mutation in our chronic distal spinal muscular atrophy patients, suggesting that spinal muscular atrophy with respiratory distress and chronic distal spinal muscular atrophy are caused by distinct genes located in the same chromosomal region. In addition, the high intrafamilial variability in age at onset raises the question of whether nonallelic modifying genes could be involved in chronic distal spinal muscular atrophy.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Genes Recessivos , Atrofia Muscular Espinal/genética , Adulto , Criança , Mapeamento Cromossômico/métodos , Doença Crônica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Feminino , Marcadores Genéticos , Humanos , Masculino , Repetições de Microssatélites/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Proteínas de Ligação a RNA , Proteínas do Complexo SMN
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