Abstract
Polyglutamine expansions in the transcriptional co-repressor ATN1, at 12p13.31, have been linked to the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed toxic gain of function. We present detailed phenotypic information on seven unrelated individuals with de novo missense and in-frame insertion variants within an evolutionarily conserved 16 amino acid ‘poly HX repeat’ motif of ATN1. The subjects have severe cognitive impairment, hypotonia, a recognisable facial gestalt and variable congenital anomalies but lack the progressive symptoms typical of DRPLA. We show that a variant in ATN1’s HX repeat is sufficient to perturb the structural features of the repeat with several effects. It alters ligand binding, including the binding to several proteins which are important in ribosomal function and regulation of gene expression. In addition, the mutation affects the nuclear localization of the HX repeat motif. These data suggest that the variant affects the transcriptional repression activity of ATN1, leading to an apparent gain of function effect. Our study provides valuable insights into the function of the HX repeat motifs and ATN1’s primary roles regulating neuronal and other organ system development. This research provides an example of phenotypically distinct allelic disorders in humans, revealing the power of unbiased genomic technologies and international collaborations in providing diagnoses for individuals with complex congenital disorders.
National Health and Medical Research; King Abdulaziz City for Science and Technology; King Salman Center for Disability Research; Saudi Human Genome Program and the King Abdullah University of Science and Technology.