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

Details

Serval ID
serval:BIB_A61CD673B3D6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.
Journal
American journal of human genetics
Author(s)
Voisin N., Schnur R.E., Douzgou S., Hiatt S.M., Rustad C.F., Brown N.J., Earl D.L., Keren B., Levchenko O., Geuer S., Verheyen S., Johnson D., Zarate Y.A., Hančárová M., Amor D.J., Bebin E.M., Blatterer J., Brusco A., Cappuccio G., Charrow J., Chatron N., Cooper G.M., Courtin T., Dadali E., Delafontaine J., Del Giudice E., Doco M., Douglas G., Eisenkölbl A., Funari T., Giannuzzi G., Gruber-Sedlmayr U., Guex N., Heron D., Holla Ø.L., Hurst ACE, Juusola J., Kronn D., Lavrov A., Lee C., Lorrain S., Merckoll E., Mikhaleva A., Norman J., Pradervand S., Prchalová D., Rhodes L., Sanders V.R., Sedláček Z., Seebacher H.A., Sellars E.A., Sirchia F., Takenouchi T., Tanaka A.J., Taska-Tench H., Tønne E., Tveten K., Vitiello G., Vlčková M., Uehara T., Nava C., Yalcin B., Kosaki K., Donnai D., Mundlos S., Brunetti-Pierri N., Chung W.K., Reymond A.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
06/05/2021
Peer-reviewed
Oui
Volume
108
Number
5
Pages
857-873
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia
Pubmed
Web of science
Create date
24/05/2021 12:59
Last modification date
12/11/2021 6:40
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