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1.
PLoS One ; 15(7): e0233582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735620

RESUMO

The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced TXNL4A expression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.


Assuntos
Processamento Alternativo , Atresia das Cóanas/patologia , Surdez/congênito , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/patologia , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Ribonucleoproteína Nuclear Pequena U5/deficiência , Spliceossomos/fisiologia , Apoptose , Diferenciação Celular , Técnicas de Reprogramação Celular , Atresia das Cóanas/genética , Células Clonais , Surdez/genética , Surdez/patologia , Transição Epitelial-Mesenquimal , Éxons/genética , Face/embriologia , Facies , Feminino , Cabeça/embriologia , Cardiopatias Congênitas/genética , Humanos , Crista Neural/citologia , Regiões Promotoras Genéticas/genética , Sítios de Splice de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Deleção de Sequência , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Via de Sinalização Wnt
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 539-542, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335881

RESUMO

OBJECTIVE: To explore the genetic basis of a proband with distinctive facial features, global developmental delay, seizures and hypoplasia of corpus callosum through next generation sequencing (NGS). METHODS: Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Whole exome and flanking sequences were screened by NGS. Suspected variants were verified by Sanger sequencing. RESULTS: The proband was found to carry a heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene, which was verified by Sanger sequencing to be a de novo variant. CONCLUSION: The heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene probably underlies the Mowat-Wilson syndrome in the proband.


Assuntos
Facies , Variação Genética , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Heterozigoto , Doença de Hirschsprung/genética , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Sequenciamento Completo do Exoma , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 567-569, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335888

RESUMO

OBJECTIVE: To explore the genotype-phenotype correlation of Cardio-facio-cutaneous syndrome (CFCS) caused by MAP2K1 gene variants. METHODS: Genomic DNA was extracted from peripheral blood sample from a child patient and his parents. Whole exome sequencing (WES) was carried out for the patient. Suspected variant was verified by Sanger sequencing. RESULTS: The patient was a 1-year-8-month old Chinese male who manifested short stature, psychomotor retardation, relative macrocephaly, distinctive facial features, and congenital heart disease. WES test revealed a heterozygous missense c.389A>G (p.Tyr130Cys) variant in the MAP2K1 gene. Sanger sequencing has confirmed the variant as de novo. According to ACMG/AMP guidelines, the variant was classified as pathogenic. CONCLUSION: Compared with previously reported CFCS cases due to MAP2K1 variants. The patient showed obvious behavioral problems, good appetite and tricuspid regurgitation, which may to be novel features for CFCS.


Assuntos
Displasia Ectodérmica , Facies , Insuficiência de Crescimento , Variação Genética , Cardiopatias Congênitas , MAP Quinase Quinase 1 , China , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Heterozigoto , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Mutação , Sequenciamento Completo do Exoma
7.
Medicine (Baltimore) ; 99(16): e19813, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311999

RESUMO

RATIONALE: Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum. PATIENT CONCERNS: The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before. DIAGNOSIS: FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing. INTERVENTIONS: The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH). OUTCOMES: The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height. LESSONS: As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.


Assuntos
Anormalidades Múltiplas/genética , Blefarofimose/diagnóstico , Contratura/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Cardiopatias Congênitas/diagnóstico , Histona-Lisina N-Metiltransferase/genética , Hipertricose/congênito , Deficiência Intelectual/genética , Microcefalia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Anormalidades da Pele/diagnóstico , Anormalidades Urogenitais/diagnóstico , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Grupo com Ancestrais do Continente Asiático/genética , Criança , Contratura/diagnóstico , Contratura/terapia , Erros de Diagnóstico , Facies , Genótipo , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/terapia , Hormônio do Crescimento/uso terapêutico , Cardiopatias Congênitas/cirurgia , Humanos , Hipertricose/diagnóstico , Hipertricose/etiologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/terapia , Masculino , Microcefalia/diagnóstico , Microcefalia/terapia , Mutação , Fenótipo , Resultado do Tratamento , Sequenciamento Completo do Exoma/métodos
8.
Adv Exp Med Biol ; 1221: 787-805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274738

RESUMO

From 1999-2003, Oxford GlycoSciences (OGS) ran a successful drug discovery oncology programme to discover small molecule inhibitors of the Heparanase I enzyme (HPSE1). HPSE1 at the time was widely regarded as being the sole mammalian enzyme capable of cleaving Heparan Sulfate (HS). A second family protein member however called Heparanase 2 (HPSE2) including splice forms was subsequently discovered by PCR analysis based on EST sequences. HPSE2 was found to be expressed mainly in smooth muscle containing tissues, particularly bladder and brain. HPSE2 is poorly expressed in haematopoietic cells and placenta which contrasts with the HPSE1 distribution pattern. HPSE2 binds more strongly to HS than HPSE1 and is believed to out compete for substrate binding and so in effect act as a tumor suppressor. So far, all attempts to show specific HPSE2 endoglycosidase activity against HS have failed suggesting that the enzyme may act as a pseudoenzyme that has evolved to retain only certain non-catalytic heparanase like functions. A breakthrough in the elucidation of functional roles for HPSE2 came about in 2010 with the linkage of HPSE2 gene deletions and mutations to the development of Ochoa/Urofacial Syndrome. Future work into the mechanistic analysis of HPSE2's role in signalling, tumor suppression and bladder/nerve functioning are needed to fully explore the role of this family of proteins.


Assuntos
Clonagem Molecular , Glucuronidase/genética , Animais , Facies , Glucuronidase/classificação , Glucuronidase/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Síndrome , Doenças Urológicas/genética
9.
Adv Exp Med Biol ; 1221: 807-819, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274739

RESUMO

Urofacial syndrome (UFS) is a rare but potentially devastating autosomal recessive disease. It comprises both incomplete urinary bladder emptying and a facial grimace upon smiling. A subset of individuals with the disease has biallelic mutations of HPSE2, coding for heparanase-2. Heparanase-2 and the classical heparanase are both detected in nerves in the maturing bladder, and mice mutant for Hpse2 have UFS-like bladder voiding defects and abnormally patterned bladder nerves. Other evidence suggests that the heparanase axis plays several roles in the peripheral and central nervous systems, quite apart from UFS-related biology. Some individuals with UFS lack HPSE2 mutations and instead carry biallelic variants of LRIG2, encoding leucine-rich-repeats and immunoglobulin-like-domains 2. Like heparanase-2, LRIG2 is detected in bladder nerves, and mutant Lrig2 mice have urination defects and abnormal patterns of bladder nerves. Further work is now needed to define the precise roles of heparanase-2 and LRIG2 in normal and abnormal neural differentiation.


Assuntos
Glucuronidase/metabolismo , Doenças Urológicas/enzimologia , Doenças Urológicas/genética , Animais , Facies , Humanos
10.
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
11.
Geobiology ; 18(5): 566-593, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196875

RESUMO

Organic and inorganic stable isotopes of lacustrine carbonate sediments are commonly used in reconstructions of ancient terrestrial ecosystems and environments. Microbial activity and local hydrological inputs can alter porewater chemistry (e.g., pH, alkalinity) and isotopic composition (e.g., δ18 Owater , δ13 CDIC ), which in turn has the potential to impact the stable isotopic compositions recorded and preserved in lithified carbonate. The fingerprint these syngenetic processes have on lacustrine carbonate facies is yet unknown, however, and thus, reconstructions based on stable isotopes may misinterpret diagenetic records as broader climate signals. Here, we characterize geochemical and stable isotopic variability of carbonate minerals, organic matter, and water within one modern lake that has known microbial influences (e.g., microbial mats and microbialite carbonate) and combine these data with the context provided by 16S rRNA amplicon sequencing community profiles. Specifically, we measure oxygen, carbon, and clumped isotopic compositions of carbonate sediments (δ18 Ocarb , δ13 Ccarb , ∆47 ), as well as carbon isotopic compositions of bulk organic matter (δ13 Corg ) and dissolved inorganic carbon (DIC; δ13 CDIC ) of lake and porewater in Great Salt Lake, Utah from five sites and three seasons. We find that facies equivalent to ooid grainstones provide time-averaged records of lake chemistry that reflect minimal alteration by microbial activity, whereas microbialite, intraclasts, and carbonate mud show greater alteration by local microbial influence and hydrology. Further, we find at least one occurrence of ∆47 isotopic disequilibrium likely driven by local microbial metabolism during authigenic carbonate precipitation. The remainder of the carbonate materials (primarily ooids, grain coatings, mud, and intraclasts) yield clumped isotope temperatures (T(∆47 )), δ18 Ocarb , and calculated δ18 Owater in isotopic equilibrium with ambient water and temperature at the time and site of carbonate precipitation. Our findings suggest that it is possible and necessary to leverage diverse carbonate facies across one sedimentary horizon to reconstruct regional hydroclimate and evaporation-precipitation balance, as well as identify microbially mediated carbonate formation.


Assuntos
Lagos , Microbiota , Isótopos de Carbono , Carbonatos , Facies , Sedimentos Geológicos , Humanos , Hidrologia , RNA Ribossômico 16S , Utah
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 459-461, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219837

RESUMO

OBJECTIVE: To explore the genetic basis for a child featuring delayed intellectual development. METHODS: The child and his parents were subjected to conventional G-banding karyotyping and single nucleotide polymorphism array (SNP-array) analysis. Suspected copy number variations (CNVs) were verified in both parents. RESULTS: No karyotypic abnormality was found with the child and his parents. SNP-array results for both parents were normal. The child was found to harbor a de novo 172 kb deletion at 18q21.2 with a physical position of 52 957 042-53 129 237. The deletion only involved one OMIM gene, namely TCF4, resulting in removal of its exons 6 to 8. CONCLUSION: The SNP-array assay has facilitated with the diagnosis of this child. Deletion of 18q21.2 region probably accounts for the Pitt-Hopkins syndrome (PTHS) in this patient.


Assuntos
Variações do Número de Cópias de DNA , Hiperventilação/genética , Deficiência Intelectual/genética , Fator de Transcrição 4/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 18/genética , Deficiências do Desenvolvimento/genética , Facies , Humanos , Fenótipo
13.
Hum Genet ; 139(4): 531-543, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030560

RESUMO

We present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool) are applied to analyze and assess the functional and phenotypic outcome of dn structural variants (dnSVs). Retrospective analysis of four phenotype-associated dnSVs identified during conventional PND precisely reveal the genomic elements disrupted by the translocation breakpoints. Identification of autosomal dominant disease due to the disruption of ANKS1B and WDR26 by t(12;17)(q23.1;q21.33)dn and t(1;3)(q24.11;p25.3)dn breakpoints, respectively, substantiated the proposed workflow. We then applied this workflow to two ongoing prenatal cases with apparently balanced dnBCAs: 46,XX,t(16;17)(q24;q21.3)dn referred for increased risk on combined first trimester screening and 46,XY,t(2;19)(p13;q13.1)dn referred due to a previous trisomy 21 pregnancy. Translocation breakpoints in the t(16;17) involve ANKRD11 and WNT3 and disruption of ANKRD11 resulted in KBG syndrome confirmed in postnatal follow-up. Breakpoints in the t(2;19) are within ATP6V1B1 and the 3' UTR of CEP89, and are not interpreted to cause disease. Genotype-phenotype correlation confirms the causative role of WDR26 in the Skraban-Deardorff and 1q41q42 microdeletion phenocopy syndromes, and that disruption of ANKS1B causes ANKS1B haploinsufficiency syndrome. In sum, we show that an liGS-based approach can be realized in PND care providing additional information concerning clinical outcomes of dnBCAs in patients with such rearrangements.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Transtornos Cromossômicos , Cromossomos Humanos/genética , Facies , Genes Dominantes , Deficiência Intelectual , Diagnóstico Pré-Natal , Anormalidades Dentárias , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Gravidez , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Fluxo de Trabalho
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 147-149, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034741

RESUMO

OBJECTIVE: To explore the genetic etiology of a girl featuring epilepsy, speech delay and mild mental retardation. METHODS: Peripheral blood samples of the child and her parents were collected. Genomic DNA was extracted and subjected to next generation sequencing. Suspected variant was confirmed by Sanger sequencing. RESULTS: The child was found to carry a de novo heterozygous c.3592G>A (p.V1198M) variant of the SMARCA2 gene, which was predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The child was diagnosed with Nicolaides-Baraitser syndrome due to heterozygous variant of the SMARCA2 gene.


Assuntos
Deformidades Congênitas do Pé/genética , Hipotricose/genética , Deficiência Intelectual/genética , Criança , Facies , Feminino , Humanos , Mutação
15.
Am J Hum Genet ; 106(3): 405-411, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109420

RESUMO

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.


Assuntos
Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Facies , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Crânio/anormalidades , Adulto Jovem
16.
Nat Neurosci ; 23(3): 375-385, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015540

RESUMO

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.


Assuntos
Transtorno do Espectro Autista/genética , Impressões Digitais de DNA , Hiperventilação/genética , Deficiência Intelectual/genética , Bainha de Mielina/genética , Transcriptoma/genética , Envelhecimento , Animais , Contagem de Células , Facies , Regulação da Expressão Gênica , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Knockout , Oligodendroglia/metabolismo , PTEN Fosfo-Hidrolase/genética , Cultura Primária de Células , Transdução de Sinais/genética , Fator de Transcrição 4/genética
17.
Pediatrics ; 145(2)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31964759

RESUMO

This set of recommendations is designed to assist the pediatrician in caring for children with Williams syndrome (WS) who were diagnosed by using clinical features and with chromosome 7 microdeletion confirmed by fluorescence in situ hybridization, chromosome microarray, or multiplex ligation-dependent probe amplification. The recommendations in this report reflect review of the current literature, including previously peer-reviewed and published management suggestions for WS, as well as the consensus of physicians and psychologists with expertise in the care of individuals with WS. These general recommendations for the syndrome do not replace individualized medical assessment and treatment.


Assuntos
Síndrome de Williams/complicações , Adolescente , Adulto , Fatores Etários , Anormalidades Cardiovasculares/etiologia , Anormalidades Cardiovasculares/terapia , Criança , Pré-Escolar , Constipação Intestinal/etiologia , Constipação Intestinal/terapia , Assistência Odontológica para Crianças/métodos , Facies , Feminino , Transtornos da Audição/etiologia , Humanos , Hipercalcemia/complicações , Hipercalcemia/diagnóstico , Hipercalcemia/terapia , Hipotireoidismo/etiologia , Lactente , Masculino , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Fotografação , Exame Físico , Comportamento Problema/psicologia , Transição para Assistência do Adulto , Sistema Urinário/anormalidades , Síndrome de Williams/genética , Síndrome de Williams/terapia , Adulto Jovem
19.
Gene ; 733: 144369, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31972311

RESUMO

MAP2K1 encodes mitogen-activated protein kinase 1 (MEK1). Mutations in MAP2K1 lead to continuous activation of MEK/ERK signaling pathway, giving rise to cardio-facio-cutaneous syndrome (CFCS). However, the molecular mechanisms of abnormal activation of MEK/ERK signaling pathway and the role of autophagy, if any, in manifesting CFCS in MAP2K mutants remain unclear. Here, we report three Chinese children with CFCS having MAP2K1 pathogenic variants, identified by exome sequencing. They presented with dysmorphic facial features, seizures, psychomotor retardation, and short stature. Additionally, the third child showed pulmonary valve stenosis, multiple skeletal deformities, and osteoporosis. Whole exome sequencing revealed two heterozygous missense mutations in exon 3 of MAP2K1 (c.383G>T; p.Gly128Val and c.389A>G; p.Tyr130Cys), as well as a novel heterozygous missense variant (c.170A>T; p.Lys57Met) in exon 2 of MAP2K1. In SH-SY5Y cells, we identified, for the first time, that MAP2K1 mutations can activate the p-ERK-dependent cell cycle progression and autophagy, and cause CFCS. Our results extended the mutational spectrum of MAP2K1, examined the role of MEK1 protein in nerve cell functions, and demonstrated, for the first time, that autophagy may mediate the altered MAP2K1 function, leading to CFCS phenotypes.


Assuntos
Autofagia , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , MAP Quinase Quinase 1/genética , Mutação , Adulto , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Criança , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Masculino , Fenótipo , Fosforilação , Células Tumorais Cultivadas
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