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1.
J Indian Soc Pedod Prev Dent ; 39(3): 329-335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34810354

RESUMO

Background: Vascular malformation of lower lip is a very rare anomaly. The lesion leads to facial asymmetry, difficulty in speech and eating and drooling of saliva. Treatment goals include symmetrical reconstruction of the lip with minimal scarring, provide adequate bulk for the reconstruction of vermillion, in toto removal of the lesion and prevent recurrence. The most common complication during surgical removal of these lesions includes blood loss and profuse bleeding which leads to poor visibility, increased operation time and postoperative requirement of blood transfusion. Therefore, the use of sclerosing agent is recommended before surgical removal. This may help in decreasing bleeding during surgery but not in all cases. Case Report: Here, we report the use of Foley's catheter for the management of a high flow lesion of lower lip in a 12-year-old patient diagnosed with Mowat-Wilson syndrome. This technique helped in providing bloodless field which lead to minimal blood loss and good visibility intraoperatively.


Assuntos
Fenda Labial , Torniquetes , Cateteres , Criança , Facies , Doença de Hirschsprung , Humanos , Deficiência Intelectual , Lábio/cirurgia , Microcefalia
2.
Nat Commun ; 12(1): 5962, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645823

RESUMO

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.


Assuntos
Haploinsuficiência , Proteínas de Homeodomínio/genética , Hiperventilação/genética , Deficiência Intelectual/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Neurônios/metabolismo , Fator de Transcrição 4/genética , Fatores de Transcrição/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzimidazóis/farmacologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Dióxido de Carbono/metabolismo , Dióxido de Carbono/farmacologia , Modelos Animais de Doenças , Facies , Regulação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Hiperventilação/tratamento farmacológico , Hiperventilação/metabolismo , Hiperventilação/patologia , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Pirazóis/farmacologia , Respiração/efeitos dos fármacos , Fator de Transcrição 4/deficiência , Fatores de Transcrição/metabolismo
3.
Environ Monit Assess ; 193(10): 623, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477949

RESUMO

The aim of the study was to assess the status of groundwater quality of Owerri and environs, for drinking and irrigation purposes. Twenty-two (22) groundwater samples were collected and analyzed for both chemical and physical compositions. The result of the study showed that groundwater in the area is of good quality for drinking purposes, except for pH and Fe, which had higher concentrations in some areas. A weak correlation matrix within the sampled parameters of the groundwater was observed. Hydrogeochemical studies revealed that 91% of the samples are within the geochemical zone of 4 (strong acids (SO4 + Cl) exceed weak acids (CO3 + HCO3)), while 9% are of the geochemical zone of 3 (weak acids (CO3 + HCO3) exceed strong acids (SO4 + Cl)). The study shows an ionic trend of Cl- > Ca2+ > HCO3- > Na+ + K+ > Mg2+ > SO42- and hydrogeochemical facies of Na-Cl, Ca-Cl, Ca-CO3, Mg-Cl, and Mg-HCO3 of 45.5%, 36.4%, 4.5%, 4.5%, and 9.1% respectively. Chloro-alkaline values were negative except for B4 which was positive. The water quality index (WQI) revealed water quality status of excellent (4.5%), good (27.3%), poor (40.9%), and very poor (27.3%). Contamination factor (CF) reveals that the groundwater is slightly polluted while the pollution load index (PLI) revealed no noticeable pollution. Gibbs diagram revealed that the entire samples are within the rock dominance zone. Irrigation suitability studies showed that SAR of the groundwater was of excellent quality; %Na had good quality (27.3%), permissible quality (45.4%), and doubtful quality (27.3%); MH had 86.4% of the groundwater suitable, while 13.6% are not suitable; KR had suitable groundwater (59.1%) and unsuitable (40.9%); while the Wilcox diagram had 72.7% excellent water for irrigation and 27.3% permissible for irrigation. A routine check of groundwater in the study area is recommended.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Monitoramento Ambiental , Facies , Humanos , Nigéria , Poluentes Químicos da Água/análise , Qualidade da Água
5.
Zhonghua Er Ke Za Zhi ; 59(7): 588-593, 2021 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-34405642

RESUMO

Objective: To explore the clinical and genetic characteristics of Noonan syndrome in children. Methods: The clinical characteristics,genetic analysis and follow-up data of 20 children diagnosed with Noonan syndrome who were admitted to Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University from March 2016 to December 2020 were retrospectively analyzed. Results: Among 20 children with Noonan syndrome, 13 were males and 7 were females. The age at diagnosis was 5.9 years (1.1 years to 12.2 years). The most common clinical complaints were delayed height growth, followed by hypospadias or cryptorchidism in 2 cases, and special facial appearance in 1 case. Physical examination revealed 12 cases of Noonan syndrome with facial features, 9 cases with cryptorchidism and hypospadias, 10 cases with abnormal cardiac structure, and 10 cases with mental retardation; Twelve patients were detected with PTPN11 variations, 4 patients carried SOS2 variations, 2 cases were confirmed with variations in SHOC2 and SOS1. Six children received recombinant human growth hormone treatment, and their height increased by 4.0 (2.5-6.0) cm to varying degrees at 9 months. No adverse events occurred. Conclusions: Male Noonan syndrome is more frequently found with external genitalia. In addition to the high frequency of PTPN11 variation, the frequency of gene variation in SOS2 gene is higher than previously reported. All of the SOS2 variations are de novo. The syndrome phenotype profiles could vary with the admitted clinical departments. To understand the full picture of the syndrome, it is necessary to collect medical information from different departments.


Assuntos
Síndrome de Noonan , Criança , Facies , Feminino , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Síndrome de Noonan/genética , Fenótipo , Estudos Retrospectivos
6.
Rev Med Liege ; 76(7-8): 625-628, 2021 Jul.
Artigo em Francês | MEDLINE | ID: mdl-34357716

RESUMO

KBG syndrome, named after the initials of the first 3 families reported, is a rare genetic syndrome caused by a deletion or a mutation of ANKRD11 (ankyrin repeat domain-containing protein 11) gene. Its prevalence is probably underestimated because of a variable expressivity; moreover, most of its clinical characteristics are not specific. There is no consensus about its diagnostic criteria. Ophthalmologic manifestations have sometimes been described among more frequent clinical signs. Early detection is critical and multidisciplinary care is requested in order to ensure the patient's independence. We report the case of a 16 years old boy diagnosed with a KBG syndrome after more than one year of genetic research, motivated by a short stature, high refractive errors and bilateral corneal clouding.


Assuntos
Deleção Cromossômica , Proteínas Repressoras , Anormalidades Múltiplas , Adolescente , Doenças do Desenvolvimento Ósseo , Facies , Humanos , Deficiência Intelectual , Masculino , Fenótipo , Proteínas Repressoras/genética , Anormalidades Dentárias
7.
BMJ Case Rep ; 14(8)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433528

RESUMO

Myhre syndrome is a rare disorder characterised by short stature, skeletal anomalies, facial dysmorphism and hearing loss (HL), resulting from heterozygous mutations of the SMAD4 gene. We describe the benefits of cochlear implant (CI) in a patient with sensorineural HL carrying a mutation (NM_005359.6: c.1498A>G; p.lle500Val) within the SMAD4 gene, detected by whole-exome sequencing. The CI was inserted through the round window despite otospongiotic abnormalities. Pure-tone audiometry improved up to 20 dBHL. Speech perception in noise (Simplified Noise Reduction - SNR +10) increased from 0% pre implantation with hearing aids to 50% post implantation. The postoperative setting of the electrical stimulation limits yielded an asymmetric map, with lower levels for central electrodes and higher levels for lateral ones. Action potential could not be evoked via medial electrodes, suggesting a cochlear nerve dysfunction. Outcomes related to quality of life and cognitive impairment improved. CI was shown to be an effective auditory rehabilitation strategy.


Assuntos
Implante Coclear , Deformidades Congênitas da Mão , Criptorquidismo , Facies , Transtornos do Crescimento , Humanos , Deficiência Intelectual , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
8.
Nat Commun ; 12(1): 4067, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210973

RESUMO

Ataxia Telangiectasia and Rad3-related (ATR) protein, as a key DNA damage response (DDR) regulator, plays an essential function in response to replication stress and controls cell viability. Hypomorphic mutations of ATR cause the human ATR-Seckel syndrome, characterized by microcephaly and intellectual disability, which however suggests a yet unknown role for ATR in non-dividing cells. Here we show that ATR deletion in postmitotic neurons does not compromise brain development and formation; rather it enhances intrinsic neuronal activity resulting in aberrant firing and an increased epileptiform activity, which increases the susceptibility of ataxia and epilepsy in mice. ATR deleted neurons exhibit hyper-excitability, associated with changes in action potential conformation and presynaptic vesicle accumulation, independent of DDR signaling. Mechanistically, ATR interacts with synaptotagmin 2 (SYT2) and, without ATR, SYT2 is highly upregulated and aberrantly translocated to excitatory neurons in the hippocampus, thereby conferring a hyper-excitability. This study identifies a physiological function of ATR, beyond its DDR role, in regulating neuronal activity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neurônios/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Nanismo , Fármacos Atuantes sobre Aminoácidos Excitatórios , Facies , Hipocampo , Camundongos , Microcefalia , Mutação , Células de Purkinje , Transdução de Sinais , Sinaptotagmina II/metabolismo
9.
BMJ Case Rep ; 14(7)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290007

RESUMO

A 20-year-old woman was referred to the diabetes clinic with type 2 diabetes diagnosed at the age of 19. Her body mass index was 31.4 kg/m2, HbA1C was 76 mmol/mol, GAD antibodies were negative with a detectable C-peptide. She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had hypothyroidism, mild intellectual disability, primary amenorrhoea and patent ductus arteriosus. Karyotyping reported normal 46XX karyotype. Genetic testing revealed a pathogenic variant in the gene encoding the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome. Type 2 diabetes has not been reported in previous cases of HIST1H1E and so this is the first reported case of type 2 diabetes with HIST1H1E syndrome.


Assuntos
Diabetes Mellitus Tipo 2 , Deficiência Intelectual , Adulto , Peptídeo C , Diabetes Mellitus Tipo 2/complicações , Facies , Feminino , Histonas , Humanos , Adulto Jovem
10.
Eur J Med Genet ; 64(9): 104287, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252586

RESUMO

BACKGROUND: The 10q26 subtelomeric microdeletion syndrome is a rare and clinically heterogeneous disorder. The precise relationships between the causative genes and the phenotype are unclear. CASE PRESENTATION: We report two new cases of 860 kb deletion of 10q26.2 identified by array CGH in a fetus with intrauterine growth retardation and his mother. The deleted region encompassed only four coding genes, DOCK1, INSYN2, NPS and FOX12. The proband had dysmorphic facies characterized by a high forehead, malformed ears, a prominent nose, and retrognathia. He had bilateral club feet, clinodactily and mild psychomotor retardation. His mother had a short stature, microcephaly, a long face with a high forehead and bitemporal narrowing, arched and sparse eyebrows, strabismus, prominent nose and chin, a thin upper lip and large protruding ears, and mild intellectual disability. CONCLUSIONS: This study presents the smallest 10q26.2 deletion so far identified, which further refines the minimal critical region associated with the 10q26 microdeletion syndrome. It focuses on three genes potentially responsible for the phenotype: DOCK1, which is the major candidate gene, and INSYN2 and NPS, which could be involved in cognitive functions.


Assuntos
Cognição , Deficiências da Aprendizagem/genética , Neuropeptídeos/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Facies , Feminino , Humanos , Lactente , Deficiências da Aprendizagem/patologia , Masculino , Fenótipo , Proteínas rac de Ligação ao GTP/genética
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(7): 663-666, 2021 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-34247373

RESUMO

OBJECTIVE: To explore gender difference in the clinical manifestations of two children with Keishi-Bukuryo-Gan syndrome (KBGS). METHODS: Clinical manifestations of the two children were reviewed. Genetic testing was carried out through next generation sequencing (NGS). Treatment was summarized, and the prognosis was followed up. RESULTS: Both children showed particular appearance including megatooth, abnormal hair distribution, hands' abnormality and language development delay. NGS revealed that both children have carried pathogenic variants of the ANKRD11 gene (c.1903_1907del and c.4911delT), which resulted in shifting of amino acid sequences starting from the Lysine and Proline at positions 635 and 1638, respectively. The female patient exhibited central precocious puberty. Her height has increased by 13 cm, and sex characteristics has retracted after treatment with leuprorelin for 23 months and recombinant human growth hormone for 1 month. CONCLUSION: Comparison of the two cases with different genders and summary of previously reported cases found that male KBGS patients have more obvious dysmorphisms such as triangular face, synophrys, ocular hypertelorism and vertebral body abnormality, with higher morbidity of epilepsy, mental retardation, autism, congenital heart disease, immune thrombocytopenia and other complications. KBGS is an autosomal dominant disease featuring more evident peculiar appearance and global development delay. Male patients often have multi-system involvement, and multidisciplinary cooperation is required for early recognition of particular features in order to improve the prognosis.


Assuntos
Deficiência Intelectual , Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Criança , Facies , Feminino , Humanos , Masculino , Fenótipo , Proteínas Repressoras/genética , Caracteres Sexuais , Anormalidades Dentárias
13.
Eur J Med Genet ; 64(9): 104267, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34161860

RESUMO

Down syndrome is one of the most common chromosomal anomalies affecting the world's population, with an estimated frequency of 1 in 700 live births. Despite its relatively high prevalence, diagnostic rates based on clinical features have remained under 70% for most of the developed world and even lower in countries with limited resources. While genetic and cytogenetic confirmation greatly increases the diagnostic rate, such resources are often non-existent in many low- and middle-income countries, particularly in Sub-Saharan Africa. To address the needs of countries with limited resources, the implementation of mobile, user-friendly and affordable technologies that aid in diagnosis would greatly increase the odds of success for a child born with a genetic condition. Given that the Democratic Republic of the Congo is estimated to have one of the highest rates of birth defects in the world, our team sought to determine if smartphone-based facial analysis technology could accurately detect Down syndrome in individuals of Congolese descent. Prior to technology training, we confirmed the presence of trisomy 21 using low-cost genomic applications that do not need advanced expertise to utilize and are available in many low-resourced countries. Our software technology trained on 132 Congolese subjects had a significantly improved performance (91.67% accuracy, 95.45% sensitivity, 87.88% specificity) when compared to previous technology trained on individuals who are not of Congolese origin (p < 5%). In addition, we provide the list of most discriminative facial features of Down syndrome and their ranges in the Congolese population. Collectively, our technology provides low-cost and accurate diagnosis of Down syndrome in the local population.


Assuntos
Reconhecimento Facial Automatizado/métodos , Síndrome de Down/patologia , Facies , Processamento de Imagem Assistida por Computador/métodos , Reconhecimento Facial Automatizado/economia , Reconhecimento Facial Automatizado/normas , República Democrática do Congo , Países em Desenvolvimento , Síndrome de Down/genética , Testes Genéticos , Humanos , Processamento de Imagem Assistida por Computador/economia , Processamento de Imagem Assistida por Computador/normas , Aprendizado de Máquina , Sensibilidade e Especificidade
14.
Eur J Med Genet ; 64(9): 104279, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34174467

RESUMO

BACKGROUND: There are few cohort studies describing the adaptive functioning profile for Pitt-Hopkins syndrome (PTHS). In this study we examine the adaptive functioning profile for PTHS and compare it to Angelman syndrome (AS). METHOD: Caregivers of 14 individuals with PTHS, 33 with deletion AS and 23 with non-deletion AS, completed the Vineland Adaptive Behavior Scales-II. RESULTS: The profile of adaptive functioning in PTHS was characterised by strengths in socialisation, followed by motor skills, communication then daily living skills. The PTHS group scored significantly lower than the non-deletion AS group on all domains except socialisation and significantly lower than the deletion AS group, for motor skills only. CONCLUSIONS: An uneven adaptive behavior profile for individuals with PTHS mirrors that of AS, with implications for assessment and intervention.


Assuntos
Adaptação Fisiológica , Hiperventilação/patologia , Deficiência Intelectual/patologia , Fenótipo , Atividades Cotidianas , Adolescente , Adulto , Síndrome de Angelman/patologia , Criança , Facies , Humanos , Destreza Motora , Comportamento Social
15.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070208

RESUMO

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat-Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Hirschsprung/imunologia , Deficiência Intelectual/imunologia , Microcefalia/imunologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/imunologia , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Facies , Feminino , Perfilação da Expressão Gênica , Haploinsuficiência , Doença de Hirschsprung/genética , Humanos , Imunidade Celular , Memória Imunológica/genética , Deficiência Intelectual/genética , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Knockout , Microcefalia/genética , Mutação , Subpopulações de Linfócitos T/imunologia , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de Zinco/deficiência , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 561-564, 2021 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-34096026

RESUMO

OBJECTIVE: To explore the genetic basis for a child suspected for Say-Barber-Biesecker-Young-Simpson syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing was carried out for the proband. Suspected variants were validated by Sanger sequencing. The impact of the variants was predicted by bioinformatic analysis. RESULTS: The child was found to harbor a de novo missense variant c.2623C>T (p.Asp875Tyr) in exon 13 of the KAT6B gene. The variant was previously unreported, and was not recorded in the major allele frequency database and predicted to be pathogenic based on PolyPhen-2, MutationTaster and PROVEAN analysis. As predicted by UCSF chimera and CASTp software, the variant can severely impact the substrate-binding pocket of histone acetyltransferase, resulting in loss of its enzymatic activity. Based on standards and guidelines by the American College of Medical Genetics and Genomics, the variant was classified to be likely pathogenic (PS2+PM2+PP3). CONCLUSION: The child's condition may be attributed to the de novo missense c.2623C>T (p.Asp875Tyr) variant of the KAT6B gene.


Assuntos
Blefarofimose , Criança , Hipotireoidismo Congênito , Facies , Feminino , Cardiopatias Congênitas , Histona Acetiltransferases/genética , Humanos , Deficiência Intelectual , Instabilidade Articular , Mutação , Fenótipo
17.
RNA ; 27(9): 1046-1067, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34162742

RESUMO

RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene EXOSC2 cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (short stature, hearing loss, retinitis pigmentosa, and distinctive facies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic EXOSC2 missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous S. cerevisiae gene RRP4 The resulting rrp4 mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in rrp4-G226D cells that model EXOSC2 p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in EXOSC2 impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.


Assuntos
Exorribonucleases/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Mutação de Sentido Incorreto , RNA Fúngico/genética , Proteínas de Ligação a RNA/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Nanismo/enzimologia , Nanismo/genética , Nanismo/patologia , Exorribonucleases/química , Exorribonucleases/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/química , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Facies , Expressão Gênica , Glicina/química , Glicina/metabolismo , Perda Auditiva/enzimologia , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Modelos Biológicos , Modelos Moleculares , Conformação Proteica , RNA Fúngico/química , RNA Fúngico/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Retinite Pigmentosa/enzimologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , Síndrome
18.
Sci Rep ; 11(1): 12861, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145321

RESUMO

DCBLD2 encodes discodin, CUB and LCCL domain-containing protein 2, a type-I transmembrane receptor that is involved in intracellular receptor signalling pathways and the regulation of cell growth. In this report, we describe a 5-year-old female who presented severe clinical features, including restrictive cardiomyopathy, developmental delay, spasticity and dysmorphic features. Trio-whole-exome sequencing and segregation analysis were performed to identify the genetic cause of the disease within the family. A novel homozygous nonsense variant in the DCBLD2 gene (c.80G > A, p.W27*) was identified as the most likely cause of the patient's phenotype. This nonsense variant falls in the extracellular N-terminus of DCBLD2 and thus might affect proper protein function of the transmembrane receptor. A number of in vitro investigations were performed on the proband's skin fibroblasts compared to normal fibroblasts, which allowed a comprehensive assessment resulting in the functional characterization of the identified DCBLD2 nonsense variant in different cellular processes. Our data propose a significant association between the identified variant and the observed reduction in cell proliferation, cell cycle progression, intracellular ROS, and Ca2 + levels, which would likely explain the phenotypic presentation of the patient as associated with lethal restrictive cardiomyopathy.


Assuntos
Anormalidades Múltiplas/genética , Cardiomiopatia Restritiva/genética , Códon sem Sentido , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Homozigoto , Proteínas de Membrana/genética , Anormalidades Múltiplas/diagnóstico , Alelos , Cálcio/metabolismo , Cardiomiopatia Restritiva/diagnóstico , Cardiomiopatia Restritiva/metabolismo , Ciclo Celular/genética , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/metabolismo , Facies , Feminino , Estudos de Associação Genética/métodos , Genoma Mitocondrial , Genômica/métodos , Humanos , Angiografia por Ressonância Magnética , Fenótipo , Radiografia Torácica , Espécies Reativas de Oxigênio/metabolismo , Sequenciamento Completo do Exoma
19.
Mar Environ Res ; 169: 105339, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33932846

RESUMO

Rhodoliths (nodular calcareous red algae) are considered one of the most important bioengineers in the Mediterranean Sea, making rhodolith beds ecologically relevant ecosystems. On the insular shelf surrounding the western Pontine Archipelago (depth from 43 to 112 m), rhodolith beds were identified through the analysis of an extensive dataset of grab samples and videos to ground-truth the backscatter acoustic facies. Six acoustic facies (low backscatter, dishomogeneous low-backscatter, dishomogeneous high-backscatter, high-backscatter, rocks and high backscatter, and rocks and medium backscatter) were recognized. We studied how rhodoliths characteristics (density, morphotype, size and structure) differently influence the backscatter signature. At the western Pontine Archipelago, rhodolith beds are mainly represented by facies dishomogeneous high backscatter, high backscatter, high backscatter with rocks, and medium backscatter with rocks. The obtained results increase both the knowledge on the heterogeneous structure of such ecologically relevant benthic habitat and highlight the use of distinctive acoustic facies for their identification. Finally, the used approach could be considered a useful method for indirect detection and mapping of rhodolith beds.


Assuntos
Ecossistema , Rodófitas , Facies , Mar Mediterrâneo
20.
J Appl Genet ; 62(3): 477-485, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33982229

RESUMO

Mowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.


Assuntos
Facies , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Polônia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
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