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1.
Am J Hum Genet ; 108(6): 1126-1137, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34010604

RESUMO

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.


Assuntos
Doenças Ósseas/etiologia , Doenças Cardiovasculares/etiologia , Doenças do Tecido Conjuntivo/etiologia , Imunidade Celular/imunologia , Mutação com Perda de Função , Perda de Heterozigosidade , beta Carioferinas/genética , Adolescente , Adulto , Animais , Doenças Ósseas/patologia , Doenças Cardiovasculares/patologia , Criança , Doenças do Tecido Conjuntivo/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem , Peixe-Zebra , beta Carioferinas/metabolismo
2.
Hum Mutat ; 43(12): 1882-1897, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35842780

RESUMO

Cornelia de Lange syndrome (CdLS; MIM# 122470) is a rare developmental disorder. Pathogenic variants in 5 genes explain approximately 50% cases, leaving the other 50% unsolved. We performed whole genome sequencing (WGS) ± RNA sequencing (RNA-seq) in 5 unsolved trios fulfilling the following criteria: (i) clinical diagnosis of classic CdLS, (ii) negative gene panel sequencing from blood and saliva-isolated DNA, (iii) unaffected parents' DNA samples available and (iv) proband's blood-isolated RNA available. A pathogenic de novo mutation (DNM) was observed in a CdLS differential diagnosis gene in 3/5 patients, namely POU3F3, SPEN, and TAF1. In the other two, we identified two distinct deep intronic DNM in NIPBL predicted to create a novel splice site. RT-PCRs and RNA-Seq showed aberrant transcripts leading to the creation of a novel frameshift exon. Our findings suggest the relevance of WGS in unsolved suspected CdLS cases and that deep intronic variants may account for a proportion of them.


Assuntos
Síndrome de Cornélia de Lange , Humanos , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/patologia , Diagnóstico Diferencial , Proteínas de Ciclo Celular/genética , Íntrons , Mutação , Análise de Sequência de RNA , Fenótipo
3.
Eur J Hum Genet ; 31(4): 461-468, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36747006

RESUMO

Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Fenótipo , Transtornos do Neurodesenvolvimento/genética , Mutação de Sentido Incorreto , Proteínas de Transporte/genética , Ubiquitina-Proteína Ligases/genética
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