A novel NEK1 variant disturbs the interaction between the C-terminal fragment of NEK1 and the VDAC1 channel, causing lethal short-rib polydactyly syndrome.

The NIMA-related kinase 1 (NEK1) gene belongs to the Never in Mitosis Gene A (NIMA) kinase family, a group whose members play essential roles in cell cycle regulation, specifically in cell division and ciliogenesis. Mutations in the NEK1 gene have been implicated in several diseases, including short-rib polydactyly syndrome (SRPS). SRPS is a bone growth disorder characterized by severe congenital anomalies. Here, we describe a family with a lethal form of SRPS due to a novel intronic variant in the NEK1 gene. Basing on whole-exome sequencing of fetuses with SRPS we identified a homozygous variant of the NEK1 gene at position c.3584-10T>A as the causative mutation. Bioinformatic methods and minigene splicing assays were then used to assess the harmfulness and functional impact of the variant. We found that the identified mutation leads to the synthesis of the NEK1 protein lacking 90C-terminal residues following the last coiled-coil region. Additional experiments were performed to identify proteins that interact with the C-terminal fragment of NEK1 absent in the mutated protein. We suggest that the interaction between the C-terminal fragment of NEK1 and the VDAC1 channel is essential for the VDAC1 phosphorylation, the absence of which is likely to affect ciliogenesis.