RESUMEN
Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.
Asunto(s)
Anomalías Múltiples/genética , Antígenos Nucleares/genética , Anomalías Craneofaciales/genética , Regulación del Desarrollo de la Expresión Génica , Haploinsuficiencia/genética , Trastornos del Desarrollo del Lenguaje/genética , Microcefalia/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Anomalías Múltiples/patología , Adolescente , Animales , Antígenos Nucleares/metabolismo , Sistemas CRISPR-Cas , Proliferación Celular , Células Cultivadas , Niño , Preescolar , Ensamble y Desensamble de Cromatina , Estudios de Cohortes , Anomalías Craneofaciales/patología , Femenino , Edición Génica , Haploinsuficiencia/fisiología , Humanos , Trastornos del Desarrollo del Lenguaje/patología , Larva/genética , Larva/crecimiento & desarrollo , Masculino , Microcefalia/patología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Fenotipo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Pez Cebra/genética , Pez Cebra/crecimiento & desarrolloRESUMEN
Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.
Asunto(s)
Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Páncreas/enzimología , Enfermedades Pancreáticas/genética , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/genética , Secuencia de Aminoácidos , Animales , Mapeo Cromosómico , Cromosomas Humanos Par 15/genética , Humanos , Anomalías Maxilofaciales/genética , Ratones , Datos de Secuencia Molecular , Mutación , Nariz/anomalías , Páncreas/patología , Enfermedades Pancreáticas/patología , SíndromeRESUMEN
OBJECTIVE: To promote a clinical entity that could be part of differential diagnosis of most disorders that affect the pediatric age group. DESCRIPTION: We describe a Brazilian girl affected by Johanson-Blizzard syndrome and review the literature. COMMENTS: Johanson-Blizzard syndrome is an autosomal recessive condition characterized by hypoplastic alae nasi, scalp defect, deafness and pancreatic insufficiency with malabsorption. Looking at the major signs, this disorder should be considered as differential diagnosis in several pediatric diseases.
RESUMEN
Objetivo: colaborar para a divulgação de uma entidade clinica pode fazer parte do diagnóstico diferencial de vários quadros que metem essa faixa etária pediátrica.Descrição: descrevemos uma criança brasileira afetada por esta condição e revemos a literatura. Comentários: a síndrome de Johanson Blizzard é uma condição autossômica recessiva, caracterizada por hipoplasia de asa nasal,agenesia de couro cabeludo, deficiência auditiva e insuficiência pancreática exócrina com má absorção. Observando os principais sinais, esta condição clínica deve ser considerada como diagnóstico diferencial em algumas doenças pediátricas