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1.
EMBO Mol Med ; 11(7): e10201, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31273937

RESUMO

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

2.
EMBO Mol Med ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171653

RESUMO

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

3.
Transfusion ; 59(4): 1367-1375, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30811032

RESUMO

BACKGROUND: We previously showed that several variations in the RHD gene, including synonymous changes, can be classified as splice site variants and may play a direct role in D variant phenotype expression. We sought to extend our study to additional candidates, notably in the first and last exons of the gene, by engineering a novel universal splice reporting vector, i.e., minigene. STUDY DESIGN AND METHODS: Our previous plasmid construct was modified to allow subcloning of any exon(s) of interest for assessing effect of variations on splicing. Seventeen novel and/or uncharacterized variations of the RHD gene were selected for the study and tested in our novel model. RESULTS: We engineered and validated a novel universal minigene for assessing virtually any variations of interest for splicing defect. Of the 17 variants tested in the novel model, 11 were shown to alter splicing either totally or partially, including the silent c.1065C>T variation, which induces major skipping of exon 7, and may therefore be responsible for reducing D antigen expression. We also showed that while all three missense variations c.1154G>C, c.1154G>T, and c.1154G>A in exon 9 are splice site variants, splicing is differentially altered and D-negative phenotype observed in the presence of the latter substitution is likely due to a defect in RhD protein folding. CONCLUSION: Overall, we hypothesize that splicing alteration is likely to be a common mechanism of D phenotype variation that has been underestimated so far. Further large-scale studies are necessary to demonstrate this statement definitely.

4.
Mol Genet Metab ; 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30660387

RESUMO

Non-syndromic microcytic congenital sideroblastic anemia (cSA) is predominantly caused by defective genes encoding for either ALAS2, the first enzyme of heme biosynthesis pathway or SLC25A38, the mitochondrial importer of glycine, an ALAS2 substrate. Herein we explored a new case of cSA with two mutations in GLRX5, a gene for which only two patients have been reported so far. The patient was a young female with biallelic compound heterozygous mutations in GLRX5 (p.Cys67Tyr and p.Met128Lys). Three-D structure analysis confirmed the involvement of Cys67 in the coordination of the [2Fe2S] cluster and suggested a potential role of Met128 in partner interactions. The protein-level of ferrochelatase, the terminal-enzyme of heme process, was increased both in patient-derived lymphoblastoid and CD34+ cells, however, its activity was drastically decreased. The activity of ALAS2 was found altered and possibly related to a defect in the biogenesis of its co-substrate, the succinyl-CoA. Thus, the patient exhibits both a very low ferrochelatase activity without any accumulation of porphyrins precursors in contrast to what is reported in erythropoietic protoporphyria with solely impaired ferrochelatase activity. A significant oxidative stress was evidenced by decreased reduced glutathione and aconitase activity, and increased MnSOD protein expression. This oxidative stress depleted and damaged mtDNA, decreased complex I and IV activities and depleted ATP content. Collectively, our study demonstrates the key role of GLRX5 in modulating ALAS2 and ferrochelatase activities and in maintaining mitochondrial function.

5.
Genome Biol Evol ; 11(2): 572-585, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668669

RESUMO

Sir4 is a core component of heterochromatin found in yeasts of the Saccharomycetaceae family, whose general hallmark is to harbor a three-loci mating-type system with two silent loci. However, a large part of the Sir4 amino acid sequences has remained unexplored, belonging to the dark proteome. Here, we analyzed the phylogenetic profile of yet undescribed foldable regions present in Sir4 as well as in Esc1, an Sir4-interacting perinuclear anchoring protein. Within Sir4, we identified a new conserved motif (TOC) adjacent to the N-terminal KU-binding motif. We also found that the Esc1-interacting region of Sir4 is a Dbf4-related H-BRCT domain, only present in species possessing the HO endonuclease and in Kluveryomyces lactis. In addition, we found new motifs within Esc1 including a motif (Esc1-F) that is unique to species where Sir4 possesses an H-BRCT domain. Mutagenesis of conserved amino acids of the Sir4 H-BRCT domain, known to play a critical role in the Dbf4 function, shows that the function of this domain is separable from the essential role of Sir4 in transcriptional silencing and the protection from HO-induced cutting in Saccharomyces cerevisiae. In the more distant methylotrophic clade of yeasts, which often harbor a two-loci mating-type system with one silent locus, we also found a yet undescribed H-BRCT domain in a distinct protein, the ISWI2 chromatin-remodeling factor subunit Itc1. This study provides new insights on yeast heterochromatin evolution and emphasizes the interest of using sensitive methods of sequence analysis for identifying hitherto ignored functional regions within the dark proteome.


Assuntos
Evolução Molecular , Proteínas Nucleares/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Proteínas de Ciclo Celular/genética , Sequência Conservada , Heterocromatina , Domínios Proteicos/genética , Saccharomyces cerevisiae
7.
Proteomics ; 18(21-22): e1800054, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30299594

RESUMO

Hydrophobic cluster analysis (HCA) is an original approach for protein sequence analysis, which provides access to the foldable repertoire of the protein universe, including yet unannotated protein segments ("dark proteome"). Foldable segments correspond to ordered regions, as well as to intrinsically disordered regions (IDRs) undergoing disorder to order transitions. In this review, how HCA can be used to give insight into this last category of foldable segments is illustrated, with examples matching known 3D structures. After reviewing the HCA principles, examples of short foldable segments are given, which often contain short linear motifs, typically matching hydrophobic clusters. These segments become ordered upon contact with partners, with secondary structure preferences generally corresponding to those observed in the 3D structures within the complexes. Such small foldable segments are sometimes larger than the segments of known 3D structures, including flanking hydrophobic clusters that may be critical for interaction specificity or regulation, as well as intervening sequences allowing fuzziness. Cases of larger conditionally disordered domains are also presented, with lower density in hydrophobic clusters than well-folded globular domains or with exposed hydrophobic patches, which are stabilized by interaction with partners.

8.
Haematologica ; 103(11): 1796-1805, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30002125

RESUMO

Hemochromatosis type 4 is one of the most common causes of primary iron overload, after HFE-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense mutations in SLC40A1 This gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous missense mutations in SLC40A1 are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare SLC40A1 variations are fortuitously observed in patients with a secondary cause of hyperferritinemia. Structure/function analysis is the most effective way of establishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We present the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevated serum ferritin concentrations and normal to low transferrin saturation levels. In vitro experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mislocalization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformational changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of-function mutations and that the study of "gating residues" is necessary in order to fully understand the action mechanism of FPN1.

9.
J Clin Invest ; 128(7): 3071-3087, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889099

RESUMO

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

10.
Blood ; 132(12): 1318-1331, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

11.
FEBS J ; 285(14): 2605-2625, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29802682

RESUMO

Over long time scales, protein evolution is characterized by modular rearrangements of protein domains. Such rearrangements are mainly caused by gene duplication, fusion and terminal losses. To better understand domain emergence mechanisms we investigated 32 insect genomes covering a speciation gradient ranging from ~ 2 to ~ 390 mya. We use established domain models and foldable domains delineated by hydrophobic cluster analysis (HCA), which does not require homologous sequences, to also identify domains which have likely arisen de novo, that is, from previously noncoding DNA. Our results indicate that most novel domains emerge terminally as they originate from ORF extensions while fewer arise in middle arrangements, resulting from exonization of intronic or intergenic regions. Many novel domains rapidly migrate between terminal or middle positions and single- and multidomain arrangements. Young domains, such as most HCA-defined domains, are under strong selection pressure as they show signals of purifying selection. De novo domains, linked to ancient domains or defined by HCA, have higher degrees of intrinsic disorder and disorder-to-order transition upon binding than ancient domains. However, the corresponding DNA sequences of the novel domains of de novo origins could only rarely be found in sister genomes. We conclude that novel domains are often recruited by other proteins and undergo important structural modifications shortly after their emergence, but evolve too fast to be characterized by cross-species comparisons alone.

12.
Cell Mol Life Sci ; 75(20): 3829-3855, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29779042

RESUMO

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/química , Modelos Moleculares , Sequência de Aminoácidos , Animais , Microscopia Crioeletrônica , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Domínios Proteicos , Estrutura Terciária de Proteína , Alinhamento de Sequência
13.
Blood Adv ; 2(1): 36-48, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29344583

RESUMO

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

14.
Hum Mutat ; 39(4): 506-514, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29271547

RESUMO

Molecules correcting the trafficking (correctors) and gating defects (potentiators) of the cystic fibrosis causing mutation c.1521_1523delCTT (p.Phe508del) begin to be a useful treatment for CF patients bearing p.Phe508del. This mutation has been identified in different genetic contexts, alone or in combination with variants in cis. Until now, 21 exonic variants in cis of p.Phe508del have been identified, albeit at a low frequency. The aim of this study was to evaluate their impact on the efficacy of CFTR-directed corrector/potentiator therapy (Orkambi). The analysis by minigene showed that two out of 15 cis variants tested increased exon skipping (c.609C > T and c.2770G > A). Four cis variants were studied functionally in the absence of p.Phe508del, one of which was found to be deleterious for protein maturation c.1399C > T (p.Leu467Phe). In the presence of p.Phe508del, this variant was the only to prevent the response to Orkambi treatment. This study showed that some patients carrying p.Phe508del complex alleles are predicted to poorly respond to corrector/potentiator treatments. Our results underline the importance to validate treatment efficacy in the context of complex alleles.

15.
J Cyst Fibros ; 17(2S): S5-S8, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28866450

RESUMO

Structural studies of the cystic fibrosis transmembrane conductance regulator (CFTR) protein are critical to understand molecular mechanisms involved in gating of the apical anion channel as well as the way in which the gating is regulated, especially by the regulatory region (R region). They are also instrumental for understanding the root cause of cystic fibrosis (CF) and supporting the development of therapeutic strategies. In this short review, we summarize recent progress in the knowledge of the CFTR 3D structure and briefly discuss implications for CF drug development.

16.
Org Lett ; 19(23): 6360-6363, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29125774

RESUMO

Highly substituted purines were synthesized in good to high yields through a one-pot straightforward metal-free scalable method, using the Traube synthesis adapted to Vilsmeier-type reagents. From 5-amino-4-chloropyrimidines, new 9-aryl-substituted chloropurines and intermediates for peptide nucleic acid synthesis were prepared. Variant procedures allowing a rapid synthesis of ribonucleosides and 7-benzylpurine from 5-amidino-6-aminopyrimidines are also reported to illustrate the high potential of this versatile toolbox. This route appears to be particularly interesting in the field of nucleic acids for a direct and rapid access to various new 8-alkylpurine nucleosides.

17.
Curr Opin Pharmacol ; 34: 112-118, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-29096277

RESUMO

Development of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators, targeting the root cause of cystic fibrosis (CF), represents a challenge in the era of personalized medicine, as CFTR mutations lead to a variety of phenotypes, which likely require different, specific treatments. CF drug development is also complicated by the need to preserve the right balance between stability and flexibility, required for optimal function of the CFTR protein. In this review, we highlight how structural data can be exploited in this context to understand the molecular mechanisms of disease-associated mutations, to characterize the mechanisms of action of known modulators and to rationalize the search for novel, specific compounds.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/química , Fibrose Cística/tratamento farmacológico , Animais , Sítios de Ligação , Simulação por Computador , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Desenho de Drogas , Humanos
18.
J Biol Chem ; 292(37): 15352-15368, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28747434

RESUMO

Bone morphogenetic proteins (BMPs) regulate diverse cellular responses during embryogenesis and in adulthood including cell differentiation, proliferation, and death in various tissues. In the adult pituitary, BMPs participate in the control of hormone secretion and cell proliferation, suggesting a potential endocrine/paracrine role for BMPs, but some of the mechanisms are unclear. Here, using a bioactivity test based on embryonic cells (C3H10T1/2) transfected with a BMP-responsive element, we sought to determine whether pituitary cells secrete BMPs or BMP antagonists. Interestingly, we found that pituitary-conditioned medium contains a factor that inhibits action of BMP-2 and -4. Combining surface plasmon resonance and high-resolution mass spectrometry helped pinpoint this factor as thrombospondin-1 (TSP-1). Surface plasmon resonance and co-immunoprecipitation confirmed that recombinant human TSP-1 can bind BMP-2 and -4 and antagonize their effects on C3H10T1/2 cells. Moreover, TSP-1 inhibited the action of serum BMPs. We also report that the von Willebrand type C domain of TSP-1 is likely responsible for this BMP-2/4-binding activity, an assertion based on sequence similarity that TSP-1 shares with the von Willebrand type C domain of Crossveinless 2 (CV-2), a BMP antagonist and member of the chordin family. In summary, we identified for the first time TSP-1 as a BMP-2/-4 antagonist and presented a structural basis for the physical interaction between TSP-1 and BMP-4. We propose that TSP-1 could regulate bioavailability of BMPs, either produced locally or reaching the pituitary via blood circulation. In conclusion, our findings provide new insights into the involvement of TSP-1 in the BMP-2/-4 mechanisms of action.


Assuntos
Proteína Morfogenética Óssea 2/antagonistas & inibidores , Proteína Morfogenética Óssea 4/antagonistas & inibidores , Modelos Moleculares , Hipófise/metabolismo , Elementos de Resposta , Trombospondina 1/metabolismo , Animais , Animais Endogâmicos , Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/sangue , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Linhagem Celular , Células Cultivadas , Biologia Computacional , Feminino , Genes Reporter , Humanos , Camundongos , Hipófise/citologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Carneiro Doméstico , Trombospondina 1/química , Trombospondina 1/isolamento & purificação
19.
Eur J Hum Genet ; 25(8): 995-1003, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28635953

RESUMO

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10-3). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10-3). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.


Assuntos
Adenosina Trifosfatases/genética , Doença de Moyamoya/genética , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases/genética , Adenosina Trifosfatases/química , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/etnologia , Domínios RING Finger/genética , Ubiquitina-Proteína Ligases/química
20.
Clin Case Rep ; 5(5): 658-663, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28469871

RESUMO

In vitro functional tests aimed to investigate CFTR dysfunction appear critical to help elucidate the functional impact of new variants of uncertain clinical significance and solve inconclusive cases, especially in early deceased newborns.

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