Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

ABSTRACT:

Background

We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects.

Methods

Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

Results

We identified an individual with a KINSSH

SUBMITTER: Bassani S 

PROVIDER: S-EPMC10827271 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature