RT Journal Article
SR Electronic
T1 Variants in the degron of <em>AFF3</em> cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 693937
DO 10.1101/693937
A1 Norine Voisin
A1 Rhonda E. Schnur
A1 Sofia Douzgou
A1 Susan M. Hiatt
A1 Cecilie F. Rustad
A1 Natasha J. Brown
A1 Dawn L. Earl
A1 Boris Keren
A1 Olga Levchenko
A1 Sinje Geuer
A1 David Amor
A1 Alfredo Brusco
A1 E. Martina Bebin
A1 Gerarda Cappuccio
A1 Joel Charrow
A1 Nicolas Chatron
A1 Gregory M. Cooper
A1 Elena Dadali
A1 Julien Delafontaine
A1 Ennio Del Giudice
A1 Ganka Douglas
A1 Tara Funari
A1 Giuliana Giannuzzi
A1 Nicolas Guex
A1 Delphine Heron
A1 Øystein L. Holla
A1 Anna C.E. Hurst
A1 Jane Juusola
A1 David Kronn
A1 Alexander Lavrov
A1 Crystle Lee
A1 Else Merckoll
A1 Anna Mikhaleva
A1 Jennifer Norman
A1 Sylvain Pradervand
A1 Victoria Sanders
A1 Fabio Sirchia
A1 Toshiki Takenouchi
A1 Akemi J. Tanaka
A1 Heidi Taska-Tench
A1 Elin Tønne
A1 Kristian Tveten
A1 Giuseppina Vitiello
A1 Tomoko Uehara
A1 Caroline Nava
A1 Binnaz Yalcin
A1 Kenjiro Kosaki
A1 Dian Donnai
A1 Stefan Mundlos
A1 Nicola Brunetti-Pierri
A1 Wendy K. Chung
A1 Alexandre Reymond
YR 2019
UL http://biorxiv.org/content/early/2019/07/17/693937.abstract
AB 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 a new autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role of AFF3 variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and 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. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif of AFF3 exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.Transcriptome analyses as well as the partial phenotypic overlap of syndromes associated with AFF3 and AFF4 variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested