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1.
Nat Commun ; 10(1): 2966, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273213

RESUMO

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteína SMARCB1/genética , Anormalidades Múltiplas/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Alelos , Animais , Criança , Pré-Escolar , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Neuroglia/patologia , Cultura Primária de Células
2.
Mol Cell ; 73(3): 562-573.e3, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30595439

RESUMO

Across eukaryotes, disruption of DNA replication causes an S phase checkpoint response, which regulates multiple processes, including inhibition of replication initiation and fork stabilization. How these events are coordinated remains poorly understood. Here, we show that the replicative helicase component Cdc45 targets the checkpoint kinase Rad53 to distinct replication complexes in the budding yeast Saccharomyces cerevisiae. Rad53 binds to forkhead-associated (FHA) interaction motifs in an unstructured loop region of Cdc45, which is phosphorylated by Rad53 itself, and this interaction is necessary for the inhibition of origin firing through Sld3. Cdc45 also recruits Rad53 to stalled replication forks, which we demonstrate is important for the response to replication stress. Finally, we show that a Cdc45 mutation found in patients with Meier-Gorlin syndrome disrupts the functional interaction with Rad53 in yeast. Together, we present a single mechanism by which a checkpoint kinase targets replication initiation and elongation complexes, which may be relevant to human disease.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Dano ao DNA , Reparo do DNA , Replicação do DNA , DNA Fúngico/biossíntese , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , Microtia Congênita/enzimologia , Microtia Congênita/genética , DNA Fúngico/genética , Proteínas de Ligação a DNA/genética , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Humanos , Micrognatismo/enzimologia , Micrognatismo/genética , Mutação , Proteínas Nucleares/genética , Patela/anormalidades , Patela/enzimologia , Fosforilação , Ligação Proteica , Pontos de Checagem da Fase S do Ciclo Celular , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética
3.
Am J Hum Genet ; 104(1): 164-178, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30580808

RESUMO

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.


Assuntos
Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Face/anormalidades , Feminino , Deformidades Congênitas da Mão/genética , Humanos , Masculino , Micrognatismo/genética , Pescoço/anormalidades , Síndrome
6.
Endocr J ; 65(2): 227-238, 2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29199204

RESUMO

Segmental progeroid syndromes with lipodystrophy are extremely rare, heterogeneous, and complex multi-system disorders that are characterized by phenotypic features of premature aging affecting various tissues and organs. In this study, we present a "sporadic/isolated" Japanese woman who was ultimately diagnosed with mandibular hypoplasia, deafness, progeroid features, and progressive lipodystrophy (MDPL) syndrome (MIM #615381) using whole exome sequencing analysis. She had been suspected as having atypical Werner syndrome and/or progeroid syndrome based on observations spanning a 30-year period; however, repeated genetic testing by Sanger sequencing did not identify any causative mutation related to various subtypes of congenital partial lipodystrophy (CPLD) and/or mandibular dysplasia with lipodystrophy (MAD). Recently, MDPL syndrome has been described as a new entity showing progressive lipodystrophy. Furthermore, polymerase delta 1 (POLD1) gene mutations on chromosome 19 have been identified in patients with MDPL syndrome. To date, 21 cases with POLD1-related MDPL syndrome have been reported worldwide, albeit almost entirely of European origin. Here, we identified a de novo mutation in exon 15 (p.Ser605del) of the POLD1 gene in a Japanese case by whole exome sequencing. To the best of our knowledge, this is the first identified case of MDPL syndrome in Japan. Our results provide further evidence that mutations in POLD1 are responsible for MDPL syndrome and serve as a common genetic determinant across different ethnicities.


Assuntos
Anormalidades Múltiplas/diagnóstico , DNA Polimerase III/genética , Surdez/complicações , Lipodistrofia/complicações , Micrognatismo/complicações , Progéria/complicações , Anormalidades Múltiplas/genética , Surdez/congênito , Surdez/diagnóstico , Surdez/genética , Diagnóstico Tardio , Diagnóstico Diferencial , Feminino , Humanos , Japão , Lipodistrofia/congênito , Lipodistrofia/diagnóstico , Lipodistrofia/genética , Mandíbula/anormalidades , Micrognatismo/diagnóstico , Micrognatismo/genética , Pessoa de Meia-Idade , Mutação , Progéria/diagnóstico , Progéria/genética , Síndrome
7.
Congenit Anom (Kyoto) ; 58(3): 105-107, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28787104

RESUMO

Coffin-Siris syndrome (CSS) is characterized by growth deficiency, intellectual disability, microcephaly, dysmorphic features, and hypoplastic nails of the fifth fingers and/or toes. Variants in the genes encoding subunits of the BAF complex as well as in SOX11 encoding the transcriptional factor under the control of BAF complex are associated with CSS. We report a new patient with a novel SOX11 mutation. He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies. Therefore, cardiac anomalies might be an important complication in patients with SOX11 mutations.


Assuntos
Anormalidades Múltiplas/genética , Coartação Aórtica/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Mutação , Pescoço/anormalidades , Fatores de Transcrição SOXC/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/patologia , Pré-Escolar , Angiografia por Tomografia Computadorizada , Ecocardiografia , Face/diagnóstico por imagem , Face/patologia , Expressão Gênica , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Micrognatismo/diagnóstico por imagem , Micrognatismo/patologia , Pescoço/diagnóstico por imagem , Pescoço/patologia , Fenótipo
8.
PLoS Genet ; 13(10): e1007041, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29036220

RESUMO

A form of dwarfism known as Meier-Gorlin syndrome (MGS) is caused by recessive mutations in one of six different genes (ORC1, ORC4, ORC6, CDC6, CDT1, and MCM5). These genes encode components of the pre-replication complex, which assembles at origins of replication prior to S phase. Also, variants in two additional replication initiation genes have joined the list of causative mutations for MGS (Geminin and CDC45). The identity of the causative MGS genetic variants strongly suggests that some aspect of replication is amiss in MGS patients; however, little evidence has been obtained regarding what aspect of chromosome replication is faulty. Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C). We find that yeast cells with the orc4Y232C allele have a prolonged S-phase, due to compromised replication initiation at the ribosomal DNA (rDNA) locus located on chromosome XII. The inability to initiate replication at the rDNA locus results in chromosome breakage and a severely reduced rDNA copy number in the survivors, presumably helping to ensure complete replication of chromosome XII. Although reducing rDNA copy number may help ensure complete chromosome replication, orc4Y232C cells struggle to meet the high demand for ribosomal RNA synthesis. This finding provides additional evidence linking two essential cellular pathways-DNA replication and ribosome biogenesis.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/genética , Replicação do DNA/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Complexo de Reconhecimento de Origem/genética , Patela/anormalidades , Proteínas de Saccharomyces cerevisiae/genética , Sequência de Aminoácidos/genética , Quebra Cromossômica , DNA Ribossômico/genética , Humanos , Mutação de Sentido Incorreto , Patela/fisiologia , RNA Ribossômico , Saccharomyces cerevisiae/genética
9.
Hum Mol Genet ; 26(21): 4168-4180, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28985365

RESUMO

Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Proteínas Nucleares/genética , Patela/anormalidades , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Proteínas de Ciclo Celular/metabolismo , Replicação do DNA , Modelos Animais de Doenças , Feminino , Mutação com Perda de Função/genética , Masculino , Proteínas Nucleares/metabolismo , Fenótipo , Origem de Replicação , Peixe-Zebra/metabolismo
10.
Am J Med Genet A ; 173(11): 3104-3108, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28884947

RESUMO

We present a 4-year-old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2-related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides-Baraitser syndrome and Coffin-Siris syndrome, providing further arguments to reclassify these disorders as "SWI/SNF-related intellectual disability syndromes."


Assuntos
Proteínas Cromossômicas não Histona/genética , Deficiência Intelectual/genética , Transtornos Motores/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Face/anormalidades , Face/patologia , Facies , Feminino , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/patologia , Predisposição Genética para Doença , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Humanos , Hipotricose/diagnóstico , Hipotricose/genética , Hipotricose/patologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Micrognatismo/diagnóstico , Micrognatismo/genética , Micrognatismo/patologia , Transtornos Motores/fisiopatologia , Pescoço/anormalidades , Pescoço/patologia
11.
J Med Case Rep ; 11(1): 237, 2017 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-28841907

RESUMO

BACKGROUND: Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome. CASE PRESENTATION: A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm (-1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G > A, p.Gly381Asp). CONCLUSIONS: In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder.


Assuntos
Artrite/genética , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Descolamento Retiniano/genética , Artrite/complicações , Artrite/diagnóstico , Catarata/diagnóstico , Catarata/etiologia , Catarata/genética , Criança , Pré-Escolar , Fissura Palatina/etiologia , Fissura Palatina/genética , Colágeno Tipo XI/deficiência , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Diagnóstico Diferencial , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Masculino , Micrognatismo/etiologia , Micrognatismo/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/etiologia , Osteocondrodisplasias/genética , Palato Mole/anormalidades , Fenótipo , Descolamento Retiniano/complicações , Descolamento Retiniano/diagnóstico
12.
Eur J Hum Genet ; 25(9): 1049-1054, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28635952

RESUMO

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.


Assuntos
Displasia Cleidocraniana/genética , Displasia Ectodérmica/genética , Deformidades Congênitas dos Membros/genética , Proteínas de Membrana/genética , Micrognatismo/genética , Mutação , Alelos , Células Cultivadas , Displasia Cleidocraniana/diagnóstico , Displasia Ectodérmica/diagnóstico , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Recém-Nascido , Inositol/metabolismo , Deformidades Congênitas dos Membros/diagnóstico , Proteínas de Membrana/metabolismo , Micrognatismo/diagnóstico , Fenótipo , Ftalimidas/farmacologia , Quinolinas/farmacologia , Vacúolos/metabolismo
13.
J Pathol ; 243(1): 9-15, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28608987

RESUMO

SMARCA4 chromatin remodelling factor is mutated in 11% of Coffin-Siris syndrome (CSS) patients and in almost all small-cell carcinoma of the ovary hypercalcaemic type (SCCOHT) tumours. Missense mutations with gain-of-function or dominant-negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole-exome sequencing to study a 15-year-old patient with mild CSS who concomitantly developed SCCOHT at age 13 years. Interestingly, our patient also showed congenital microphthalmia, which has never previously been reported in CSS patients. We detected a de novo germline heterozygous nonsense mutation in exon 19 of SMARCA4 (c.2935C > T;p.Arg979*), and a somatic frameshift mutation in exon 6 (c.1236_1236delC;p.Gln413Argfs*88), causing complete loss of SMARCA4 immunostaining in the tumour. The immunohistochemical findings are supported by the observation that the c.2935C > T mutant transcript was detected by reverse transcription polymerase chain reaction at a much lower level than the wild-type allele in whole blood and the lymphoblastoid cell line of the proband, confirming nonsense-mediated mRNA decay. Accordingly, immunoblotting demonstrated that there was approximately half the amount of SMARCA4 protein in the proband's cells as in controls. This study suggests that SMARCA4 constitutional mutations associated with CSS are not necessarily non-truncating, and that haploinsufficiency may explain milder CSS phenotypes, as previously reported for haploinsufficient ARID1B. In addition, our case supports the dual role of chromatin remodellers in developmental disorders and cancer, as well as the involvement of SMARCA4 in microphthalmia, confirming previous findings in mouse models and the DECIPHER database. Finally, we speculate that mild CSS might be under-recognized in a proportion of SCCOHT patients harbouring SMARCA4 mutations. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Anormalidades Múltiplas/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Pequenas/genética , Códon sem Sentido , DNA Helicases/genética , Face/anormalidades , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Hipercalcemia/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Microftalmia/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/metabolismo , Adolescente , Biomarcadores Tumorais/análise , Western Blotting , Carcinoma de Células Pequenas/química , Carcinoma de Células Pequenas/diagnóstico , DNA Helicases/análise , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/metabolismo , Heterozigoto , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/metabolismo , Imuno-Histoquímica , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/metabolismo , Masculino , Micrognatismo/diagnóstico , Micrognatismo/metabolismo , Microftalmia/diagnóstico , Microftalmia/metabolismo , Pessoa de Meia-Idade , Proteínas Nucleares/análise , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Linhagem , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/análise
14.
Hum Mutat ; 38(10): 1365-1371, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28649782

RESUMO

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to ß-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.


Assuntos
Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Adolescente , Criança , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Exoma , Face , Feminino , Deformidades Congênitas da Mão/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/genética , Micrognatismo/fisiopatologia , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , Ligação Proteica , Fatores de Transcrição/genética
15.
J Clin Res Pediatr Endocrinol ; 9(4): 355-359, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28387648

RESUMO

We describe the case of a 7-year-old girl referred to our diabetes unit for hyperglycemia associated with facial dysmorphic features, intellectual disability, and cerebral cavernomas. Based on presence of anti islet antigen-2 (IA2) antibodies and a human leukocyte antigen of DR3/DR4/DQ2, the patient was initially diagnosed to be a case of type 1 diabetes mellitus. At follow-up, the very good metabolic control on a low insulin dose and negative IA2 antibodies led to a suspicion of glucokinase (GCK)-related maturity-onset diabetes of the young (MODY 2). This suspicion was substantiated in multiplex ligation-dependent probe amplification (MLPA) which showed a heterozygous GCK deletion (exons 1 to 12). However, the patient's parents did not have such a deletion and were clinically euglycemic. Given the clinical picture and the MLPA findings, array based comparative genomic hybridization was performed showing a monoallelic deletion of 7.23 Mb in the short arm of chromosome 7 (7p13-p12.1). The deleted intervals contain 39 genes listed in the Online Mendelian Inheritance in Man list, including GCK associated with MODY 2, CCM2 associated with type 2 cerebral cavernous malformations, IGFBP-3 associated with decrease in postnatal growth, and OGD associated with alpha-ketoglutarate dehydrogenase deficiency, with cognitive impairment and movement abnormalities. This previously unreported deletion was considered to explain the clinical picture of the patient. Also, the findings suggest that 7p13-p12.1 contains genes involved in intellectual disability and craniofacial development.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7 , Anormalidades Craniofaciais/genética , Hiperglicemia/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Costelas/anormalidades , Criança , Anormalidades Craniofaciais/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hiperglicemia/complicações , Deficiência Intelectual/complicações , Micrognatismo/complicações
16.
Am J Med Genet A ; 173(4): 938-945, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28328130

RESUMO

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.


Assuntos
Otopatias/diagnóstico , Orelha/anormalidades , Predisposição Genética para Doença , Micrognatismo/diagnóstico , Mutação , Fosfolipase C beta/genética , Síndrome de Pierre Robin/diagnóstico , Adulto , Criança , Orelha/patologia , Otopatias/classificação , Otopatias/genética , Otopatias/patologia , Endotelina-1/genética , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Expressão Gênica , Genes Dominantes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Micrognatismo/classificação , Micrognatismo/genética , Micrognatismo/patologia , Linhagem , Fenótipo , Síndrome de Pierre Robin/classificação , Síndrome de Pierre Robin/genética , Síndrome de Pierre Robin/patologia , Terminologia como Assunto
17.
J Cardiol ; 70(5): 504-510, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28336205

RESUMO

BACKGROUND: Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. METHODS: This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0±17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats>2000/24h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. RESULTS: In KCNJ2 mutation carriers vs non-carriers (n=25 vs n=19) significant differences were observed in U-wave manifestations in V2-V4, Tpeak-Tend duration, QTUc duration (p<0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n=9), in those with arrhythmias and/or syncope and/or CA (n=16) micrognathia (p=0.004), periodic paralysis (p=0.019), palpitation (p=0.005), U-wave n V2-V4 (p=0.049) were more frequent; QTU (p=0.045) and Tpeak-Tend (p=0.014) were also longer (n=9). In the subgroup of carriers with syncope and/or cardiac arrest (n=10, 90% women), K897T-KCNH2 polymorphism (p=0.02), periodic paralysis (p=0.004), muscle weakness (p=0.04), palpitations (p=0.04), arrhythmias (biventricular VT, p=0.003; polymorphic VT, p=0.009) were observed more frequently. Tpeak-Tend duration was longer (p=0.007) and the percentage of patients with premature ventricular contraction >2000/24h was higher (p=0.005). CONCLUSION: A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged Tpeak-Tend time. Our findings suggest that K897T may contribute to the occurrence of syncope.


Assuntos
Síndrome de Andersen/genética , Canal de Potássio ERG1/genética , Síncope/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos , Parada Cardíaca/complicações , Parada Cardíaca/genética , Humanos , Masculino , Micrognatismo/complicações , Micrognatismo/genética , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Polimorfismo Genético , Síncope/complicações , Taquicardia Ventricular/complicações , Taquicardia Ventricular/genética , Complexos Ventriculares Prematuros/complicações , Complexos Ventriculares Prematuros/genética , Adulto Jovem
18.
J Hum Genet ; 62(8): 741-746, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28250421

RESUMO

KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin-Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Face/anormalidades , Variação Genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Adulto , Criança , Pré-Escolar , Facies , Feminino , Humanos , Masculino , Fenótipo , Prognóstico
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 34(1): 68-72, 2017 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-28186598

RESUMO

OBJECTIVE: To identify the genetic cause for a 11-year-old Chinese boy with Meier-Gorlin syndrome (MGS). METHODS: Chromosomal microarray analysis (CMA) was used to detect potential variations, while whole exome sequencing (WES) was used to identify sequence variants. Sanger sequencing was used to confirm the suspected variants. RESULTS: The boy has featured short stature, microtia, small patella, slender body build, craniofacial anomalies, and small testes with normal gonadotropin. A complete uniparental disomy of chromosome 16 was revealed by CMA. WES has identified a novel homozygous mutation c.67A>G (p.Lys23Glu) in ORC6 gene mapped to chromosome 16. As predicted by Alamut functional software, the mutation may affect the function of structural domain of the ORC6 protein. CONCLUSION: The patient is probably the first diagnosed MGS case in China, who carried a novel homozygous mutation of the ORC6 gene and uniparental disomy of chromosome 16. The effect of this novel mutation on the growth and development needs to be further investigated.


Assuntos
Cromossomos Humanos Par 16/genética , Microtia Congênita/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Mutação , Complexo de Reconhecimento de Origem/genética , Patela/anormalidades , Dissomia Uniparental/genética , Sequência de Bases , Criança , Saúde da Família , Pai , Heterozigoto , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA/métodos
20.
Eur J Hum Genet ; 25(5): 646-650, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28198391

RESUMO

Meier-Gorlin syndrome (MGORS) is a rare disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recessive mutations in ORC1, ORC4, ORC6, CDT1, CDC6, and CDC45, encoding members of the pre-replication (pre-RC) and pre-initiation (pre-IC) complexes, and heterozygous mutations in GMNN, a regulator of cell-cycle progression and DNA replication, have already been associated with this condition. We performed whole-exome sequencing (WES) in a patient with a clinical diagnosis of MGORS and identified biallelic variants in MCM5. This gene encodes a subunit of the replicative helicase complex, which represents a component of the pre-RC. Both variants, a missense substitution within a conserved domain critical for the helicase activity, and a single base deletion causing a frameshift and a premature stop codon, were predicted to be detrimental for the MCM5 function. Although variants of MCM5 have never been reported in specific human diseases, defect of this gene in zebrafish causes a phenotype of growth restriction overlapping the one associated with orc1 depletion. Complementation experiments in yeast showed that the plasmid carrying the missense variant was unable to rescue the lethal phenotype caused by mcm5 deletion. Moreover cell-cycle progression was delayed in patient's cells, as already shown for mutations in the ORC1 gene. Altogether our findings support the role of MCM5 as a novel gene involved in MGORS, further emphasizing that this condition is caused by impaired DNA replication.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Patela/anormalidades , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Criança , Códon sem Sentido , Microtia Congênita/diagnóstico , Replicação do DNA , Exoma , Teste de Complementação Genética , Transtornos do Crescimento/diagnóstico , Humanos , Mutação INDEL , Masculino , Micrognatismo/diagnóstico , Mutação de Sentido Incorreto , Saccharomyces cerevisiae/genética
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