Isoform-specific regulation of SMARCAD1 dosage in ectodermal homeostasis and dysplasia

Haploinsufficiency is a common cause of developmental disorders, yet the mechanisms regulating protein abundance of dosage-sensitive genes remain incompletely understood. SMARCAD syndrome comprises inherited ectodermal dysplasias caused by mutations affecting SMARCAD1-s, the skin-specific short isoform of the ATP-dependent chromatin remodeller SMARCAD1. Here, we show that independent patient-derived mutations impair splicing of this isoform, resulting in intron retention. Although total mRNA abundance is reduced, spliced transcripts remain translationally competent and yield variably reduced levels of wild-type protein, providing evidence for a threshold-dependent haploinsufficiency model of disease. Under physiological conditions, the isoform-specific non-coding exon 1 dampens protein production without altering transcript levels, revealing previously unrecognized post-transcriptional control of SMARCAD1-s dosage. Our findings implicate upstream open reading frames as candidate mediators of translational control. Unexpectedly, SMARCAD1-s exhibits regulated nucleocytoplasmic distribution. Functional analyses identify two nuclear localization signals that differentially contribute to localization of the SMARCAD1 isoforms. Together, our findings clarify the molecular basis of SMARCAD syndrome and identify post-transcriptional and spatial mechanisms controlling the abundance and localization of a dosage-sensitive chromatin remodeller, providing insight into protein dosage control.