Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
Am J Hum Genet ; 108(9): 1669-1691, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34314705

RESUMEN

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.


Asunto(s)
Discapacidades del Desarrollo/genética , Proteínas de Drosophila/genética , Enfermedades Hereditarias del Ojo/genética , Discapacidad Intelectual/genética , Carioferinas/genética , Anomalías Musculoesqueléticas/genética , beta Carioferinas/genética , Proteína de Unión al GTP ran/genética , Alelos , Secuencia de Aminoácidos , Animales , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Enfermedades Hereditarias del Ojo/metabolismo , Enfermedades Hereditarias del Ojo/patología , Femenino , Dosificación de Gen , Regulación del Desarrollo de la Expresión Génica , Genoma Humano , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Carioferinas/antagonistas & inhibidores , Carioferinas/metabolismo , Masculino , Anomalías Musculoesqueléticas/metabolismo , Anomalías Musculoesqueléticas/patología , Mutación , Neuronas/metabolismo , Neuronas/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Secuenciación Completa del Genoma , beta Carioferinas/metabolismo , Proteína de Unión al GTP ran/metabolismo
2.
Am J Hum Genet ; 108(3): 502-516, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33596411

RESUMEN

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.


Asunto(s)
Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos X/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ARN/genética , Adolescente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/fisiopatología , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Haploinsuficiencia/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Adulto Joven
3.
Am J Hum Genet ; 104(3): 530-541, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30827496

RESUMEN

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Trastorno Autístico/etiología , Discapacidad Intelectual/etiología , Mutación Missense , Proteínas Nucleares/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Pronóstico , Homología de Secuencia , Síndrome , Adulto Joven
4.
Am J Hum Genet ; 98(5): 963-970, 2016 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-27087320

RESUMEN

Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.


Asunto(s)
Anomalías Múltiples/etiología , Proteínas Portadoras/genética , Trastornos de los Cromosomas/etiología , Discapacidades del Desarrollo/etiología , Haploinsuficiencia/genética , Mutación/genética , Animales , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 1 , Femenino , Humanos , Lactante , Masculino , Ratones , Fenotipo , Pronóstico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA