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  Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., et al. (2021). Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. The American Journal of Human Genetics, 108(5), 857-873. doi:10.1016/j.ajhg.2021.04.001.

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Voisin, Norine , Author
Schnur, Rhonda E., Author
Douzgou , Sofia , Author
Hiatt, Susan M., Author
Rustad, Cecilie F. , Author
Brown, Natasha J., Author
Earl, Dawn L., Author
Keren, Boris, Author
Levchenko, Olga , Author
Geuer, Sinje, Author
Verheyen, Sarah , Author
Johnson , Diana , Author
Zarate, Yuri A., Author
Hančárová, Miroslava, Author
Amor, David J., Author
Bebin, E. Martina , Author
Blatterer, Jasmin, Author
Brusco, Alfredo , Author
Cappuccio, Gerarda , Author
Charrow, Joel , Author
Chatron, Nicolas , AuthorCooper, Gregory M., AuthorCourtin, Thomas , AuthorDadali, Elena, AuthorDelafontaine, Julien , AuthorDel Giudice, Ennio , AuthorDoco, Martine, AuthorDouglas, Ganka, AuthorEisenkölbl, Astrid , AuthorFunari, Tara, AuthorGiannuzzi , Giuliana , AuthorGruber-Sedlmayr, Ursula , AuthorGuex, Nicolas, AuthorHeron, Delphine, AuthorHolla, Øystein L. , AuthorHurst, Anna C. E. , AuthorJuusola, Jane, AuthorKronn, David, AuthorLavrov, Alexander , AuthorLee, Crystle, AuthorLorrain, Séverine , AuthorMerckoll, Else, AuthorMikhaleva, Anna , AuthorNorman, Jennifer, AuthorPradervand, Sylvain, AuthorPrchalová, Darina , AuthorRhodes, Lindsay, AuthorSanders , Victoria R. , AuthorSedláček, Zdeněk , AuthorSeebacher , Heidelis A. , AuthorSellars, Elizabeth A. , AuthorSirchia, Fabio, AuthorTakenouchi, Toshiki , AuthorTanaka, Akemi J. , AuthorTaska-Tench, Heidi , AuthorTønne, Elin, AuthorTveten, Kristian , AuthorVitiello, Giuseppina , AuthorVlčková , Markéta , AuthorUehara, Tomoko , AuthorNava, Caroline, AuthorYalcin, Binnaz , Author Kosaki, Kenjiro, AuthorDonnai, Dian , AuthorMundlos, Stefan1, Author              Brunetti-Pierri, Nicola , AuthorChung, Wendy K. , AuthorReymond, Alexandre, Author more..
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              


Free keywords: AFF3; AFF4; horseshoe kidney; intellectual disability; mesomelic dysplasia
 Abstract: The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.


 Dates: 2021-03-292021-05-062021-05-06
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.ajhg.2021.04.001
 Degree: -



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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
Publ. Info: American Society of Human Genetics
Pages: 17 Volume / Issue: 108 (5) Sequence Number: - Start / End Page: 857 - 873 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1