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1.
Nat Genet ; 50(3): 344-348, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483653

RESUMO

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

2.
Genes (Basel) ; 7(12)2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27916860

RESUMO

Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

3.
Neuromuscul Disord ; 26(9): 570-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27450922

RESUMO

Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S). We report three families variably affected by IGHMBP2 mutations. Patient 1, an 8-year-old boy with two homozygous variants: c.2T>C and c.861C>G, was wheelchair bound due to sensorimotor axonal neuropathy and chronic respiratory failure. Patient 2 and his younger sister, Patient 3, had compound heterozygous variants: c.983_987delAAGAA and c.1478C>T. However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months. Patient 4, a 6-year-old girl homozygous for IGHMBP2 c.449+1G>T documented to result in two aberrant transcripts, was wheelchair dependent due to axonal polyneuropathy. The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/metabolismo , Fatores de Transcrição/genética , Criança , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Lactente , Masculino , Fenótipo , Insuficiência Respiratória/genética , Insuficiência Respiratória/metabolismo , Irmãos
4.
Eur J Med Genet ; 59(6-7): 342-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27182039

RESUMO

Mitochondrial DNA depletion syndromes (MTDPS) represent a clinically and genetically heterogeneous group of autosomal recessive disorders, caused by mutations in genes involved in maintenance of mitochondrial DNA (mtDNA). Biallelic mutations in FBXL4 were recently described to cause encephalomyopathic MTDPS13. The syndrome has infantile onset and presents with hypotonia, feeding difficulties, a pattern of mild facial dysmorphisms, global developmental delay and brain atrophy. Laboratory investigations reveal elevated blood lactate levels, unspecific mitochondrial respiratory chain (MRC) enzyme deficiencies and mtDNA depletion. We report a novel missense variant, c.1442T > C (p.Leu481Pro), in FBXL4 (NM_012160.4) in a Norwegian boy with clinical, biochemical and cerebral MRI characteristics consistent with MTDPS13. The FBXL4 c.1442T > C (p.Leu481Pro) variant was not present in public databases, 149 Norwegian controls nor an in-house database containing whole exome sequencing data from 440 individuals, and it was predicted in silico to be deleterious to the protein function. Activities of MRC enzymes were normal in muscle tissue (complexes I-IV) and cultured skin fibroblasts (complexes I-V) from the patient, but mtDNA depletion was confirmed in muscle, thus supporting the predicted pathogenicity of the FBXL4 c.1442T > C (p.Leu481Pro) variant. On clinical indication of mitochondrial encephalomyopathy, sequencing of FBXL4 should be performed, even when the activity levels of the MRC enzymes are normal.


Assuntos
DNA Mitocondrial/genética , Proteínas F-Box/genética , Encefalomiopatias Mitocondriais/genética , Músculo Esquelético/patologia , Ubiquitina-Proteína Ligases/genética , Criança , Exoma/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Encefalomiopatias Mitocondriais/epidemiologia , Encefalomiopatias Mitocondriais/patologia , Mutação de Sentido Incorreto , Noruega/epidemiologia
5.
BMC Med Genet ; 16: 113, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26684006

RESUMO

BACKGROUND: Pathogenic mutations in FBN1, encoding the glycoprotein, fibrillin-1, cause Marfan syndrome (MFS) and related connective tissue disorders. In the present study, qualitative and quantitative effects of 16 mutations, identified in FBN1 in MFS patients with systematically described phenotypes, were investigated in vitro. METHODS: Qualitative analysis was performed with reverse transcription-PCR (RT-PCR) and gel electrophoresis, and quantitative analysis to determine the FBN1 mRNA levels in fibroblasts from the 16 patients with MFS was performed with real-time PCR. RESULTS: Qualitative analysis documented that the mutations c.4817-2delA and c.A4925G led to aberrant FBN1 mRNA splicing leading to in frame deletion of exon 39 and in exon 39, respectively. No difference in the mean FBN1 mRNA level was observed between the entire group of cases and controls, nor between the group of patients with missense mutations and controls. The mean expression levels associated with premature termination codon (PTC) and splice site mutations were significantly lower than the levels in patients with missense mutations. A high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in three of his first degree relatives. No association was indicated between the FBN1 transcript level and specific phenotypic manifestations. CONCLUSIONS: Abnormal FBN1 transcripts were indicated in fibroblasts from patients with the splice site mutation c.4817-2delA and the missense mutation c.A4925G. While the mean FBN1 mRNA expression level in fibroblasts from patients with splice site and PTC mutations were lower than the mean level in patients with missense mutations and controls, inter-individual variability was high. The observation that high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in the family suggests that variable expression of the normal FBN1 allele may contribute to explain the variability in FBN1 mRNA level.


Assuntos
Fibroblastos/metabolismo , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , RNA Mensageiro/genética , Sequência de Bases , Células Cultivadas , Análise Mutacional de DNA , Fibrilina-1 , Fibrilinas , Predisposição Genética para Doença/genética , Genótipo , Humanos , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Mutação , Mutação de Sentido Incorreto , Sítios de Splice de RNA/genética , Processamento de RNA/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência
6.
Mol Cytogenet ; 8: 57, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26236398

RESUMO

We report two unrelated patients with overlapping chromosome 2q13 deletions (patient 1 in chr2:111415137-113194067 bp and patient 2 in chr2:110980342-113007823 bp, hg 19). Patient 1 presents with developmental delay, microcephaly and mild dysmorphic facial features, and patient 2 with autism spectrum disorder, borderline cognitive abilities, deficits in attention and executive functions and mild dysmorphic facial features. The mother and maternal grandmother of patient 1 were healthy carriers of the deletion. Previously, 2q13 deletions were reported in 27 patients, and the interpretation of its clinical significance varied. Our findings support that the 2q13 deletion is associated with a developmental delay syndrome manifesting with variable expressivity and reduced penetrance which poses a challenge for genetic counselling as well as the clinical recognition of 2q13 deletion patients.

7.
Hum Mol Genet ; 24(20): 5845-54, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26220973

RESUMO

Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.


Assuntos
Condrodisplasia Punctata Rizomélica/genética , Mutação da Fase de Leitura , Peroxissomos/metabolismo , Transporte Proteico/genética , Receptores Citoplasmáticos e Nucleares/genética , Adolescente , Adulto , Criança , Condrodisplasia Punctata Rizomélica/metabolismo , Exoma , Feminino , Humanos , Lactente , Masculino , Linhagem , Receptor 1 de Sinal de Orientação para Peroxissomos , Peroxissomos/genética , Isoformas de Proteínas , Receptores Citoplasmáticos e Nucleares/metabolismo , Análise de Sequência de DNA
8.
Am J Med Genet A ; 167A(3): 657-63, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25691420

RESUMO

A pair of sisters was ascertained for multiple congenital defects, including marked craniofacial dysmorphisms with blepharophimosis, and severe psychomotor delay. Two novel compound heterozygous mutations in UBE3B were identified in both the sisters by exome sequencing. These mutations include c.1A>G, which predicts p.Met1?, and a c.1773delC variant, predicted to cause a frameshift at p.Phe591fs. UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. We report on the thorough clinical examination of the patients and review the state of art knowledge of this disorder.


Assuntos
Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Heterozigoto , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Fenótipo , Ubiquitina-Proteína Ligases/genética , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Exoma , Facies , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Linhagem
9.
Eur J Med Genet ; 57(9): 513-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24911659

RESUMO

2p15p16.1-deletion syndrome was first described in 2007 based on the clinical presentation of two patients. The syndrome is characterized by intellectual disability, autism spectrum disorders, microcephaly, dysmorphic facial features and a variety of congenital organ defects. The precise genotype-phenotype correlation in 2p15-deletion syndrome is not understood. However, greater insight can be obtained by thorough clinical investigation of patients carrying deletions, especially those of small size. We report a 21-year-old male patient with features overlapping the clinical spectrum of the 2p15p16.1-deletion syndrome, such as intellectual disability, dysmorphic facial features, and congenital defects. He carried a 230 kb de novo deletion (chr2:61500346-61733075 bp, hg19), which affects the genes USP34, SNORA70B and XPO1. While there is a lack of functional data on SNORA70B, the involvement of USP34 and XPO1 in the regulation of fundamental developmental processes is well known. We suggest that haploinsufficiency of one or both of these genes is likely to be responsible for the disease in our patient.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2 , Anormalidades Craniofaciais/genética , Haploinsuficiência , Deficiência Intelectual/genética , Carioferinas/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteases Específicas de Ubiquitina/genética , Adulto , Hibridização Genômica Comparativa , Facies , Heterogeneidade Genética , Humanos , Cariotipagem , Masculino , Fenótipo , Adulto Jovem
10.
Am J Med Genet A ; 161A(5): 1137-42, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23463539

RESUMO

The transcription factor SOX3 is widely expressed in early vertebrate brain development. In humans, duplication of SOX3 and polyalanine expansions at its C-terminus may cause intellectual disability and hypopituitarism. Sox3 knock-out mice show a variable phenotype including structural and functional anomalies affecting the branchial arches and midline cerebral structures such as the optic chiasm and the hypothalamo-pituitary axis. SOX3 is claimed to be required in normal brain development and function in mice and humans, as well as in pituitary and craniofacial development. We report on an 8-year-old boy with a 2.1 Mb deletion in Xq27.1q27.2, which was found to be inherited from his healthy mother. To our knowledge, this is the smallest deletion including the entire SOX3 gene in a male reported to date. He is mildly intellectually disabled with language delay, dysarthria, behavior problems, minor facial anomalies, and hyperphagia. Hormone levels including growth, adrenocorticotropic and thyroid stimulating hormones are normal. Magnetic resonance imaging (MRI) at age 6 years showed no obvious brain anomalies. Genetic redundancy between the three members of the B1 subfamily of SOX proteins during early human brain development likely explains the apparently normal development of brain structures in our patient who is nullisomic for SOX3.


Assuntos
Encéfalo/anormalidades , Deficiências do Desenvolvimento/genética , Hiperfagia/genética , Deficiência Intelectual/genética , Fatores de Transcrição SOXB1/genética , Criança , Análise Citogenética , Humanos , Masculino , Reação em Cadeia da Polimerase , Deleção de Sequência
11.
Orphanet J Rare Dis ; 8: 3, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23294540

RESUMO

BACKGROUND: Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes. METHODS AND RESULTS: We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes. CONCLUSIONS: Patients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.


Assuntos
Cromossomos Humanos Par 6 , Haploinsuficiência , Histonas/metabolismo , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Complexo Repressor Polycomb 2/genética , Adolescente , Ataxina-1 , Ataxinas , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Marcha , Humanos , Cariotipagem , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Deleção de Sequência
12.
Eur J Med Genet ; 55(12): 695-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22986108

RESUMO

We report a 11 year old male patient ascertained for mild intellectual disability and minor dysmorphic features, carrying a 1 Mb de novo deletion on chromosome 11q13.1q13.2 detected by aCGH. This is the first report of a deletion in this region in a patient presenting with intellectual impairment and mild dysmorphic traits. The 1 Mb deleted area encompasses 47 RefSeq genes, including Cornichon homologue 2 (CNIH2), Cofilin-1 (CFL1) and neuronal PAS domain-containing protein 4 (NPAS4), which are highly expressed in the central nervous system. Knockout of the CNIH2 and CFL1 orthologues in animals results in migration disturbances, while low or no expression of Npas4 in mice results in impairment of memory and learning. These three genes have previously been suggested as candidate genes for neurological disorders.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 11 , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Criança , Facies , Deformidades Congênitas da Mão/genética , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo
13.
Eur J Med Genet ; 53(4): 221-4, 2010 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20382277

RESUMO

We report on a 11-year-old boy investigated for a clinical suspicion of Angelman syndrome (AS) (OMIM 105830) who was found to carry a de novo interstitial deletion of chromosome 15q13.2q13.3. The deletion overlaps the critical region for the newly recognized recurrent 15q13.3 deletion syndrome. This is the first report of a patient with 15q13.3 deletion syndrome with clinical features similar to that of AS, thus broadening the phenotypic spectrum associated with the 15q13.3 microdeletion syndrome.


Assuntos
Síndrome de Angelman/genética , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Adulto , Síndrome de Angelman/patologia , Criança , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo
14.
Mol Biotechnol ; 45(2): 116-20, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20119685

RESUMO

Gene silencing by RNA interference (RNAi) is a widely used approach for target-specific knockdown of gene expression. Induction of RNAi in mammalian cells can be achieved by introduction of synthetic small interfering RNA (siRNA) resulting in transient knockdown, or alternatively by stable expression of short hairpin RNA (shRNA). Several algorithms for efficient siRNA design exist, but recent reports have suggested that these cannot be directly used to design efficient shRNAs. In this study, 25 siRNAs targeting independent sequences in five transcripts were used for the construction of shRNA cassettes. Both the siRNAs and shRNA constructs were transfected into HEK293T cells. Quantitative real-time PCR analysis revealed that 19 out of the 25 shRNA constructs reduced the average expression level to less than 30%. Our data support that sequences designed by siRNA algorithms efficiently reduce the expression of the target gene when converted into shRNA expression constructs.


Assuntos
Técnicas de Silenciamento de Genes/métodos , RNA Interferente Pequeno/genética , Algoritmos , Sequência de Bases , Linhagem Celular , DNA Intergênico/genética , Expressão Gênica/genética , Inativação Gênica , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA/genética , Interferência de RNA , RNA Interferente Pequeno/química , Relação Estrutura-Atividade
15.
Tidsskr Nor Laegeforen ; 128(17): 1951-5, 2008 Sep 11.
Artigo em Norueguês | MEDLINE | ID: mdl-18787571

RESUMO

BACKGROUND: The human genome contains a large number of single nucleotide polymorphisms (SNPs) that contribute to normal variation of human traits. Many SNPs have also been shown to affect the development and predisposition of disease. Comparisons of genomes have recently shown that also large DNA segments can vary in structure and number of copies between individuals. A large number of duplications, deletions and inversions has been detected, ranging in size from a few thousand to several millions base pairs. Here we describe the structural variations detected in the human genome, their impact on normal phenotypic variation in the population, and how differences in genome structure may contribute to development of disease. MATERIAL AND METHODS: This article is based on studies of literature retrieved through a non-systematic search of PubMed. RESULTS AND INTERPRETATION: Many structural variations in the genome overlap with genes. Duplications and deletions may change the copy number of genes, and inversions may disrupt gene structure. Some of the affected genes contribute to phenotypic variation between healthy individuals, while others can predispose to disease or contribute to disease development. Diseases caused by such structural variations constitute a major health problem in the population.


Assuntos
Variação Genética , Genoma Humano/genética , Deleção Cromossômica , Duplicação Gênica , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
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