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1.
Am J Hum Genet ; 110(5): 774-789, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37054711

RESUMO

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.


Assuntos
Proteínas de Drosophila , Doenças do Sistema Nervoso , Adulto , Animais , Humanos , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Mutação/genética , RNA Mensageiro
2.
Am J Med Genet A ; 185(10): 2863-2872, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34050707

RESUMO

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23). The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA. Our cohort of patients, gathered through GeneMatcher, exhibited features including tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The individuals presented in this article provide evidence of a syndrome related to alterations in DDX23 characterized predominantly by atypical neurodevelopment.


Assuntos
Transtorno do Espectro Autista/genética , RNA Helicases DEAD-box/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Instabilidade Genômica/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Splicing de RNA/genética , RNA de Cadeia Dupla/genética , Convulsões/complicações , Convulsões/genética , Convulsões/fisiopatologia
3.
Eur J Med Genet ; 63(10): 104019, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712214

RESUMO

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been described as an autosomal-dominant disorder caused by mutations in the NR2F1 gene, whose common characteristics include developmental delay, intellectual disability, optic nerve atrophy, hypotonia, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity and thinning of the corpus callosum. Missense mutations in NR2F1 have been reported to be the major cause of BBSOAS. A possible genotype-phenotype correlation has been considered with missense mutations affecting the ligand-binding domain of NR2F1 as well as whole-gene deletions of NR2F1 showing a milder phenotype of BBSOAS. Here we report on a patient with a novel frameshift mutation in NR2F1 showing the full spectrum of BBOAS indicating an expanded clinical spectrum and a reconsideration of the observed genotype-phenotype correlation.


Assuntos
Transtorno do Espectro Autista/genética , Fator I de Transcrição COUP/genética , Deficiência Intelectual/genética , Atrofias Ópticas Hereditárias/genética , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/fisiopatologia , Sequência de Bases , Criança , Mutação da Fase de Leitura , Estudos de Associação Genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Hipotonia Muscular/genética , Mutação de Sentido Incorreto , Atrofias Ópticas Hereditárias/diagnóstico por imagem , Atrofias Ópticas Hereditárias/fisiopatologia , Fenótipo , Mutação Puntual , Convulsões/genética
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