English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Open

Presents the pdf analysis as premium feature

PDF Analysis

Insights

Presents the summarisation as premium feature

Summarisation

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

We identifiedde novononsense variants inKIDINS220/ARMSin three unrelated patients with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO). KIDINS220 is an essential scaffold protein coordinating neurotrophin signal pathways in neurites and is spatially and temporally regulated in the brain. Molecular analysis of patients’ variants confirmed expression and translation of truncated transcripts similar to recently characterized alternative terminal exon splice isoforms ofKIDINS220.KIDINS220undergoes extensive alternative splicing in specific neuronal populations and developmental time points, reflecting its complex role in neuronal maturation. In mice and humans,KIDINS220is alternative spliced in the middle region as well as in the last exon. These full-length andKIDINS220splice variants occur at precise moments in cortical, hippocampal, and motor neuron development, with splice variants similar to the variants seen in our patients and lacking the last exon ofKIDINS220occurring in adult rather than in embryonic brain. We conducted tissue-specific expression studies in zebrafish that resulted in spasms, confirming a functional link with disruption of the KIDINS220 levels in developing neurites. This work reveals a crucial physiological role ofKIDINS220in development and provides insight into how perturbation of the complex interplay ofKIDINS220isoforms and their relative expression can affect neuron control and human metabolism. Altogether, we here show thatde novoprotein-truncatingKIDINS220variants cause a new syndrome, SINO. This is the first report ofKIDINS220variants causing a human disease.

Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity