Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.
Am J Hum Genet
; 108(6): 1126-1137, 2021 06 03.
Article
en En
| MEDLINE
| ID: mdl-34010604
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Óseas
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Enfermedades Cardiovasculares
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Enfermedades del Tejido Conjuntivo
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Pérdida de Heterocigocidad
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Beta Carioferinas
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Mutación con Pérdida de Función
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Inmunidad Celular
Tipo de estudio:
Risk_factors_studies
Límite:
Adolescent
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Adult
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Animals
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Child
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Female
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Revista:
Am J Hum Genet
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia