Mutational scanning of <i>CRX</i> classifies clinical variants and reveals biochemical properties of the transcriptional effector domain.

ABSTRACT: The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substituti

SUBMITTER: Shepherdson JL 

PROVIDER: S-EPMC11529990 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature