PUBLICATION
Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
- Authors
- 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, A.C.E., 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.
- ID
- ZDB-PUB-210508-3
- Date
- 2021
- Source
- American journal of human genetics 108: 857-873 (Journal)
- Registered Authors
- Keywords
- AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia
- MeSH Terms
-
- Adolescent
- Amino Acid Sequence
- Animals
- Brain Diseases/etiology
- Brain Diseases/genetics*
- Child
- Child, Preschool
- Epilepsy/complications
- Epilepsy/genetics*
- Evolution, Molecular
- Female
- Fused Kidney/genetics*
- Gene Frequency
- Humans
- Infant
- Intellectual Disability/genetics*
- Male
- Mice
- Models, Molecular
- Mutation, Missense*
- Nuclear Proteins/chemistry
- Nuclear Proteins/deficiency
- Nuclear Proteins/genetics*
- Osteochondrodysplasias/genetics*
- Phenotype
- Protein Stability
- Syndrome
- Transcriptional Elongation Factors/chemistry
- Transcriptional Elongation Factors/genetics
- Young Adult
- Zebrafish/genetics
- PubMed
- 33961779 Full text @ Am. J. Hum. Genet.
Citation
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, A.C.E., 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. (2021) Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. American journal of human genetics. 108:857-873.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping