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

Voisin, Norine; Schnur, Rhonda E.; Douzgou, Sofia; Hiatt, Susan M.; Rustad, Cecilie F.; Brown, Natasha J; Earl, Dawn; Keren, Boris; Levchenko, Olga A.; Geuer, Sinje; Verheyen, Sarah; Johnson, Diana; Zárate, Yuri A.; Hančárová, Miroslava; Amor, David J.; Bebin, E. Martina; Blatterer, Jasmin; Brusco, Alfredo; Cappuccio, Gerarda; Charrow, Joel; Chatron, Nicolas; Cooper, Gregory M.; Courtin, Thomas; Дадали, Е. Л.; Delafontaine, Julien; Giudice, Ennio Del; Doco, Martine; Douglas, Ganka; Eisenkölbl, Astrid; Funari, Tara; Giannuzzi, Giuliana; Gruber-Sedlmayr, U; Guex, Nicolas; Héron, Delphine; Holla, Øystein L.; Hurst, Anna; Juusola, Jane; Kronn, David; Лавров, А. В.; Lee, Crystle; Lorrain, Séverine; Merckoll, Else; Mikhaleva, Anna; Norman, Jennifer; Pradervand, Sylvain; Prchalová, Darina; Rhodes, Lindsay; Sanders, Victoria R.; Sedláček, Zdeněk; Seebacher, Heidelis A.; Sellars, Elizabeth A.; Sirchia, Fabio; Tamura, Toshiki; Tanaka, Akemi; Taska-Tench, Heidi; Tønne, Elin; Tveten, Kristian; Vitiello, Giuseppina; Vlčková, Markéta; Uehara, Tomoko; Nava, Caroline; Yalcin, Binnaz; Kosaki, Kenjiro; Mundlos, Stefan; Brunetti‐Pierri, Nicola; Chung, Wendy K.; Reymond, Alexandre

doi:10.1016/j.ajhg.2021.04.001

Cited by 22 publications

(67 citation statements)

References 62 publications

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“…Interestingly, all missense variants located to the ALF domain of AFF3, similar to AFF4 missense variants ( Raible et al, 2019 ). However, in contrast to the reported AFF4 variants, AFF3 protein stability was not affected ( Voisin et al, 2021 ). Together with the observed gene deletions, this suggests that AFF3 heterozygous LoF causes the observed phenotype.…”

Section: Super Elongation Complexmentioning

confidence: 89%

“…Dosing SEC-activity in Drosophila neuroblasts is essential to maintain the right balance between self-renewal and differentiation ( Liu et al, 2017 ). Perhaps unsurprisingly, mutations in SEC subunits lead to neurodevelopmental syndromes such as Fragile XE ID, CHOPS and KINSSHIP syndrome ( Pramparo et al, 2005 ; Striano et al, 2005 ; Izumi et al, 2015 ; Voisin et al, 2021 ).…”

Section: Super Elongation Complexmentioning

confidence: 99%

“…To date, AFF3 deletions (2) and missense (16) variants have been identified in 18 individuals with developmental delay and intellectual disability ( Steichen-Gersdorf et al, 2008 ; Shimizu et al, 2019 ; Voisin et al, 2021 ). Interestingly, all missense variants located to the ALF domain of AFF3, similar to AFF4 missense variants ( Raible et al, 2019 ).…”

Section: Super Elongation Complexmentioning

confidence: 99%

“…Besides developmental delay and intellectual disability, most patients carrying AFF3 variants presented with encephalopathy, skeletal dysplasia, failure to thrive, microcephaly and global brain atrophy ( Steichen-Gersdorf et al, 2008 ; Shimizu et al, 2019 ; Voisin et al, 2021 ). Despite similarity to CHOPS, specific characteristics suggested a novel syndrome called KINSSHIP for horseshoe kidney, Nievergelt/Savarirayan type of mesomelic dysplasia, seizures, hypertrichosis, intellectual disability, and pulmonary involvement (OMIM# 619297) ( Voisin et al, 2021 ). AFF3 missense variants or deletions cause a much more severe phenotype than FRA2A-associated AFF3 gene silencing.…”

Section: Super Elongation Complexmentioning

confidence: 99%

“…AFF3 missense variants or deletions cause a much more severe phenotype than FRA2A-associated AFF3 gene silencing. This could be explained by a lack of AFF3 inactivation in the first few weeks after fertilization ( Willemsen et al, 2002 ) or, alternatively, AFF3 silencing could be tissue specific ( Voisin et al, 2021 ).…”

Section: Super Elongation Complexmentioning

confidence: 99%

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Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

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Section: Super Elongation Complexmentioning

confidence: 89%

Section: Super Elongation Complexmentioning

confidence: 99%

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Molecular evolution of transcription factors AF4/FMR2 family member (AFF) gene family and the role of lamprey AFF3 in cell proliferation

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Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather-pecking behavior

2022

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Feather pecking (FP) is a damaging nonaggressive behavior in laying hens with a heritable component. Its occurrence has been linked to the immune system, the circadian clock, and foraging behavior. Furthermore, dysregulation of miRNA biogenesis, disturbance of the gamma-aminobutyric acid (GABAergic) system, as well as neurodevelopmental deficiencies are currently under debate as factors influencing the propensity for FP behavior. Past studies, which focused on the dissection of the genetic factors involved in FP, relied on single nucleotide polymorphisms (SNPs) and short insertions and deletions < 50 bp (InDels). These variant classes only represent a certain fraction of the genetic variation of an organism. Hence, we reanalyzed whole-genome sequencing data from two experimental populations, which have been divergently selected for FP behavior for over more than 15 generations, performed variant calling for structural variants (SVs) as well as tandem repeats (TRs), and jointly analyzed the data with SNPs and InDels. Genotype imputation and subsequent genome-wide association studies, in combination with expression quantitative trait loci analysis, led to the discovery of multiple variants influencing the GABAergic system. These include a significantly associated TR downstream of the GABA receptor subunit beta-3 (GABRB3) gene, two microRNAs targeting several GABA receptor genes, and dystrophin (DMD), a direct regulator of GABA receptor clustering. Furthermore, we found the transcription factor ETV1 to be associated with the differential expression of 23 genes, which points toward a role of ETV1, together with SMAD4 and KLF14, in the disturbed neurodevelopment of high-feather pecking chickens.

show abstract

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

Cited by 22 publications

References 62 publications

Transcription Pause and Escape in Neurodevelopmental Disorders

Transcription Pause and Escape in Neurodevelopmental Disorders

Molecular evolution of transcription factors AF4/FMR2 family member (AFF) gene family and the role of lamprey AFF3 in cell proliferation

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather-pecking behavior

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