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1.
Nat Commun ; 11(1): 4673, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938917

RESUMO

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.


Assuntos
Proteínas de Ligação a DNA/genética , Haploinsuficiência , Sistema de Sinalização das MAP Quinases/genética , Síndrome de Noonan/etiologia , Fatores de Transcrição/genética , Proteínas ras/metabolismo , Anormalidades Múltiplas/genética , Animais , Deleção Cromossômica , Cromossomos Humanos Par 6 , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo Correpressor Histona Desacetilase e Sin3/genética , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo , Fatores de Transcrição/metabolismo , Proteínas ras/genética
2.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32822602

RESUMO

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Assuntos
Atrofia/genética , Doenças Cerebelares/genética , Deficiência Intelectual/genética , Lisina Acetiltransferase 5/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/fisiopatologia , Pré-Escolar , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Processamento de Proteína Pós-Traducional/genética
3.
Nat Commun ; 11(1): 4287, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855419

RESUMO

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.


Assuntos
Anormalidades Múltiplas/etiologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Quadruplex G , Troca de Cromátide Irmã , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proliferação de Células , RNA Helicases DEAD-box/química , DNA Helicases/química , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estabilidade Proteica , Pseudogenes , RNA Helicases/genética , RNA Helicases/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Síndrome , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Am J Hum Genet ; 107(3): 514-526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32791035

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.


Assuntos
Anormalidades Múltiplas/genética , Astenozoospermia/genética , Axonema/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anormalidades Múltiplas/patologia , Alelos , Animais , Astenozoospermia/fisiopatologia , Axonema/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Homozigoto , Humanos , Infertilidade Masculina/patologia , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microtúbulos/genética , Mitocôndrias/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
5.
Medicine (Baltimore) ; 99(29): e20574, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702813

RESUMO

RATIONALE: Schaaf-Yang syndrome, a rare imprinted hereditary disease caused by MAGEL2 variants, manifests as developmental delay/intellectual disability, neonatal hypotonia, feeding difficulties, contractures, and autism spectrum disorder. PATIENT CONCERNS: Patient 1 and 2 were infant girls presenting facial dysmorphisms, contractures of interphalangeal joints, neonatal hypotonia, feeding difficulties, congenital heart diseases, and respiratory complications. Besides, Patient 2 presented with delayed psychomotor development. DIAGNOSIS: Whole-exome sequencing was performed and heterozygous mutations of the MAGEL2 gene were detected in the patients. They were diagnosed as Schaaf-Yang syndrome. INTERVENTIONS: The patients received supportive treatment including mechanical ventilation, parenteral nutrition and gastric tube feeding. OUTCOMES: Whole-exome sequencing revealed de novo heterozygous c.1996dupC pathogenic mutations in the MAGEL2 gene in the 2 patients. They died due to respiratory failure at the age of 20 days and 98 days, respectively. LESSONS: Our results indicate that MAGEL2 variants can cause congenital heart disease and fatal respiratory complications, broadening the phenotypic spectrum and adding to the fatal cases of Schaaf-Yang syndrome. We highly suggest that the MAGEL2 gene should be added to gene-panels or gene-filters in next-generation sequencing-based diagnostics, which is of great significance for early diagnosis and early intervention of Schaaf-Yang syndrome patients.


Assuntos
Anormalidades Múltiplas/genética , Testes Genéticos/métodos , Proteínas/genética , Sequenciamento Completo do Exoma/métodos , Criança , Contratura/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Evolução Fatal , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Feminino , Articulações dos Dedos/fisiopatologia , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/genética , Atrofia Muscular/genética , Cuidados Paliativos , Insuficiência Respiratória/genética , Síndrome
6.
Am J Hum Genet ; 107(2): 330-341, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32619401

RESUMO

Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men. Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants, variants which were either absent or rare in the control human population and were predicted to be deleterious by multiple bioinformatic tools. Re-analysis of exome data from a second cohort of 167 MMAF-affected men from France, Iran, and North Africa permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant. DNAH8 encodes a dynein axonemal heavy-chain component that is expressed preferentially in the testis. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella. Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17. Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility. Interestingly, intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes. Collectively, our experimental observations from humans and mice demonstrate that DNAH8 is essential for sperm flagellar formation and that bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF.


Assuntos
Anormalidades Múltiplas/genética , Dineínas do Axonema/genética , Flagelos/genética , Variação Genética/genética , Infertilidade Masculina/genética , Cauda do Espermatozoide/patologia , Alelos , Animais , Estudos de Coortes , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Espermatozoides/anormalidades , Testículo/anormalidades , Sequenciamento Completo do Exoma/métodos
7.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
8.
Tunis Med ; 98(5): 420-422, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32548846

RESUMO

Cystic Fibrosis (CF) is a lethal autosomal recessive condition due to a defect at the level of the transmembrane conductance regulator gene which plays a role in cell homeostasis. Numerous mutations have been identified as the cause of this gene defect, with delF508 being one of the most common mutations in Tunisia. This is a case report describing, up to our knowledge, the second case of a patient with CF carrying a rare mutation: W19X. W19X is a nonsense mutation that has been previously identified in only one other Tunisian patient with CF. Since both incidence of this mutation have been described in Tunisia, it seems as if W19X is specific to Tunisian CF patient with significant morbidities. The information provided by this study contributes to defining the molecular spectrum of CF in Tunisia, in the aim of improving genetic testing and prenatal diagnosis.


Assuntos
Códon sem Sentido , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Fibrose Cística/diagnóstico , Fibrose Cística/patologia , Frequência do Gene , Testes Genéticos , Humanos , Triptofano/genética , Tunísia
9.
Cytogenet Genome Res ; 160(6): 309-315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32599602

RESUMO

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Cromossomos Humanos Par 2/genética , Córnea/anormalidades , Homozigoto , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Dissomia Uniparental/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Catarata/genética , Feminino , Humanos , Lactente , Perda de Heterozigosidade/genética , Masculino , Pais , Polimorfismo de Nucleotídeo Único/genética , Proteínas rab3 de Ligação ao GTP/genética
10.
Gene ; 753: 144778, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32439377

RESUMO

Several genes are associated with the multiple morphological abnormalities of the sperm flagella (MMAF) syndrome, including QRICH2, CFAP43, CFAP44, CFAP69, CCDC39, and AKAP4 genes. Although previous work has shown that these genes are significantly associated with male reproductive traits in certain species, it is not yet known whether they are associated with reproductive traits in the goat. In this study, we investigated the correlations between 47 putative indel mutations in MMAF- associated genes, and first-born litter sizes in 1479 Shaanbei white cashmere (SBWC) goats. Our analysis showed that five of these indel mutations were polymorphic: QRICH2-P4, CFAP43-P20, CFAP69-P4, CFAP69-P6, and CFAP69-P7. Association analysis revealed that only a 6-bp indel variation within CFAP43 (CFAP43-P20) was strongly significantly associated with litter sizes in SBWC goats (P = 0.000). We also identified a significant difference in the genotypic distribution between the mothers of single lambs and the mothers of multiple lambs (P = 0.001); carriers of the DD genotype had greater litter sizes than carriers of the II or ID genotype. Our analysis also revealed 8-bp and 6-bp indels in CFAP69 (CFAP69-P4 and CFAP69-P6, respectively) that were in complete linkage disequilibrium with each other (D' = 0.99, r2 = 1.00). These findings indicate that the 6-bp indel mutation in the CFAP43 gene can be used as an effective molecular marker for selecting reproductive traits in goat breeding operations.


Assuntos
Tamanho da Ninhada de Vivíparos/genética , Proteínas dos Microtúbulos/genética , Cauda do Espermatozoide/metabolismo , Anormalidades Múltiplas/genética , Animais , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Flagelos/genética , Flagelos/metabolismo , Estudos de Associação Genética , Genótipo , Cabras/genética , Mutação INDEL/genética , Infertilidade Masculina/genética , Masculino , Mutação , Fenótipo , Reprodução , Espermatozoides/metabolismo
11.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
12.
Hum Genet ; 139(11): 1363-1379, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32424618

RESUMO

We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome.


Assuntos
Deficiência Intelectual/genética , Linfocinas/genética , Mutação/genética , Anormalidades Múltiplas/genética , Adolescente , Animais , Criança , Éxons/genética , Humanos , Masculino , Fenótipo , Isoformas de Proteínas/genética , Síndrome , Fatores de Transcrição/genética
14.
BMC Med Genet ; 21(1): 70, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245430

RESUMO

BACKGROUND: Mutations in GATA6 are the most frequent cause of pancreatic agenesis. Most cases present with neonatal diabetes mellitus. CASE PRESENTATION: The case was a female born after an uncomplicated pregnancy and delivery in a non-consanguineous family (3.59 kg, 70th percentile). Severe cardiac malformations were diagnosed at two and a half months old. No hyperglycaemic episodes were recorded in the neonatal period. Diabetes was diagnosed at 21 years due to the detection of incidental glycosuria. She had a low but detectable C-peptide level at diagnosis. Anti-GAD and Islet-cell antibodies were negative and she failed oral hypoglycaemic therapy and was started on insulin. Abdominal MRI revealed the absence of most of the neck, body, and tail of pancreas with normal pancreas elastase levels. Criteria for type 1 or type 2 diabetes were not fulfilled, therefore a next generation sequencing (NGS) panel was performed. A novel heterozygous pathogenic GATA6 mutation (p.Tyr235Ter) was identified. The GATA6 variant was not detected in her parents, implying that the mutation had arisen de novo in the proband. CONCLUSION: Rarely GATA6 mutations can cause adult onset diabetes. This report highlights the importance of screening the GATA6 gene in patients with adult-onset diabetes, congenital cardiac defects and pancreatic agenesis with no first-degree family history of diabetes. It also emphasizes the importance of genetic counselling in these patients as future offspring will be at risk of inheriting the variant and developing GATA6 anomalies.


Assuntos
Anormalidades Múltiplas/genética , Diabetes Mellitus Tipo 2/genética , Fator de Transcrição GATA6/genética , Cardiopatias Congênitas/genética , Mutação , Pâncreas/anormalidades , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Cardiopatias Congênitas/complicações , Humanos , Lactente , Recém-Nascido , Transtornos de Início Tardio , Linhagem , Adulto Jovem
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 509-513, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335874

RESUMO

OBJECTIVE: To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transporte Vesicular , Cerebelo/anormalidades , Anormalidades do Olho , Testes Genéticos , Doenças Renais Císticas , Proteínas de Membrana , Diagnóstico Pré-Natal , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Variação Genética , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Gravidez
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 532-534, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335879

RESUMO

OBJECTIVE: To delineate the nature and origin of chromosomal aberration in a boy with mental retardation and multiple congenital deformities. METHODS: Chromosomal karyotypes of the proband and his parents were determined by routine G-banding analysis. Genomic DNA was also analyzed with single nucleotide polymorphism array (SNP array). RESULTS: The karyotype of the proband was 46,X,add(Y)(q11.23). No karyotypic abnormality was detected in either parent. SNP array has identified a de novo 21.6 Mb duplication at 22q12qter in the proband. CONCLUSION: The de novo 22q12qter duplication probably underlies the abnormalities in the proband.


Assuntos
Anormalidades Múltiplas , Cromossomos Humanos Par 22 , Trissomia , Anormalidades Múltiplas/genética , Adulto , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 22/genética , Feminino , Testes Genéticos , Humanos , Deficiência Intelectual/genética , Cariotipagem , Masculino
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 555-558, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335885

RESUMO

OBJECTIVE: To explore the genetic basis for an infant with multiple malformations including congenital heart disease and cleft palate. METHODS: The child and his parents were subjected to conventional chromosomal karyotyping and low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis. RESULTS: The infant was found to have a 46,X,add(Y)(q11.23) karyotype, and his CNV-seq result was seq [hg19] 22q12.1q13.3 (29 520 001-51 180 000)× 3. His parents were found to be normal by both methods. CONCLUSION: The additional chromosomal material found on Yq, verified as duplication of 22q12.1-q13.3, may account for the abnormal phenotype in this infant. CNV-seq has provided a useful complement for the diagnosis and more accurate information for genetic counseling.


Assuntos
Anormalidades Múltiplas , Duplicação Cromossômica , Cromossomos Humanos Par 22 , Anormalidades Múltiplas/genética , Criança , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Variações do Número de Cópias de DNA , Testes Genéticos , Cardiopatias Congênitas/genética , Humanos , Lactente , Cariotipagem
18.
Nature ; 580(7801): 124-129, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32238941

RESUMO

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation1. Despite recent advances in in vitro induction of major mesodermal lineages and cell types2,3, experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR-Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.


Assuntos
Relógios Biológicos/fisiologia , Desenvolvimento Embrionário/fisiologia , Células-Tronco Pluripotentes/citologia , Somitos/citologia , Somitos/crescimento & desenvolvimento , Anormalidades Múltiplas/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Relógios Biológicos/genética , Desenvolvimento Embrionário/genética , Edição de Genes , Regulação da Expressão Gênica no Desenvolvimento/genética , Glicosiltransferases/deficiência , Glicosiltransferases/genética , Hérnia Diafragmática/genética , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Fenótipo , Somitos/metabolismo , Fatores de Tempo
19.
Medicine (Baltimore) ; 99(15): e19751, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282736

RESUMO

RATIONALE: This case report expands the mutation and phenotypic spectra of Beaulieu-Boycott-Innes syndrome (BBIS), and will be valuable for mutation-based pre- and post-natal screening of BBIS when conducting a genetic diagnosis. PATIENT CONCERNS: A 4-year old boy from Guilin City, Guangxi Zhuang Autonomous Region, China, was referred to our clinic for clarification of his diagnosis because he showed moderate intellectual disability. DIAGNOSIS: Two novel compound heterozygous mutations of THOC6, c.664T>C (p.Trp222Arg) and c.945+1 G>A were identified in this patient by whole exome sequencing. The two mutations were evaluated as pathogenic and likely pathogenic respectively according to the American College of Medical Genetics guidelines. This is the first case displaying the BBIS phenotype reported in the Chinese population. These two mutations have not been reported previously. INTERVENTIONS: Symptomatic treatment and rehabilitation training for patients. OUTCOMES: The genetic cause of the disease was identified. The family received scientific genetic counseling. LESSONS: BBIS is a rare syndromic autosomal recessive disease with intellectual disability and it is normally difficult for clinicians to recognize it. Whole exome sequencing is an efficient way to identify the gene which causes a particular disease in patients.


Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Proteínas de Ligação a RNA/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/reabilitação , Anormalidades Múltiplas/terapia , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/reabilitação , Deficiências do Desenvolvimento/terapia , Facies , Aconselhamento Genético/normas , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/reabilitação , Deficiência Intelectual/terapia , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/reabilitação , Atrofia Muscular/terapia , Mutação/genética , Fenótipo , Síndrome , Sequenciamento Completo do Exoma/métodos
20.
Clin Sci (Lond) ; 134(8): 941-953, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227118

RESUMO

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Diarreia/congênito , Células Epiteliais/metabolismo , Erros Inatos do Metabolismo/genética , Trocador 3 de Sódio-Hidrogênio/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Animais , Diarreia/genética , Diarreia/metabolismo , Diarreia/mortalidade , Diarreia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/patologia , Camundongos , Camundongos Knockout , Mutação , Trocador 3 de Sódio-Hidrogênio/metabolismo
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