Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling. - Université de Lille Accéder directement au contenu
Article Dans Une Revue Genetics in Medicine Année : 2022

Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling.

S. Alawbathani
  • Fonction : Auteur
M. Asif
  • Fonction : Auteur
G. Baujat
  • Fonction : Auteur
C. Becker
  • Fonction : Auteur
B. Budde
  • Fonction : Auteur
L. Gallacher
  • Fonction : Auteur
T. Georgomanolis
  • Fonction : Auteur
W. Höhne
  • Fonction : Auteur
S. Lyonnet
  • Fonction : Auteur
I. A. Ba-Saddik
  • Fonction : Auteur
S. Manouvrier-Hanu
  • Fonction : Auteur
S. Motameny
  • Fonction : Auteur
A. A. Noegel
  • Fonction : Auteur
L. Pais
  • Fonction : Auteur
P. Wagle
  • Fonction : Auteur
S. M. White
  • Fonction : Auteur
M. Willems
  • Fonction : Auteur
P. Nürnberg
  • Fonction : Auteur

Résumé

Purpose LEF1 encodes a transcription factor acting downstream of the WNT-β-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 variants. Methods High-throughput sequencing was employed to delineate the genetic underpinnings of the disease. Cellular consequences were characterized by immunofluorescence, immunoblotting, pulldown assays, and/or RNA sequencing. Results Monoallelic variants in LEF1 were detected in 11 affected individuals from 4 unrelated families, and a biallelic variant was detected in an affected individual from a consanguineous family. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Depending on the type and location of LEF1 variants, the inheritance of this novel Mendelian condition can be either autosomal dominant or recessive. Our functional data indicate that 2 molecular mechanisms are at play: haploinsufficiency or loss of DNA binding are responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants is associated with a severe phenotype. Transcriptomic studies reveal an alteration of WNT signaling. Conclusion Our findings establish mono- and biallelic variants in LEF1 as a cause for a novel syndrome comprising limb malformations and ectodermal dysplasia.

Dates et versions

hal-04616906 , version 1 (05-07-2024)

Identifiants

Citer

William Dufour, S. Alawbathani, Anne-Sophie Jourdain, M. Asif, G. Baujat, et al.. Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling.. Genetics in Medicine, 2022, Genetics in Medicine, 24 (8), pp.1708-1721. ⟨10.1016/j.gim.2022.04.022⟩. ⟨hal-04616906⟩

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