Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.
Kour S., Rajan DS., Fortuna TR., Anderson EN., Ward C., Lee Y., Lee S., Shin YB., Chae J-H., Choi M., Siquier K., Cantagrel V., Amiel J., Stolerman ES., Barnett SS., Cousin MA., Castro D., McDonald K., Kirmse B., Nemeth AH., Rajasundaram D., Innes AM., Lynch D., Frosk P., Collins A., Gibbons M., Yang M., Desguerre I., Boddaert N., Gitiaux C., Rydning SL., Selmer KK., Urreizti R., Garcia-Oguiza A., Osorio AN., Verdura E., Pujol A., McCurry HR., Landers JE., Agnihotri S., Andriescu EC., Moody SB., Phornphutkul C., Sacoto MJG., Begtrup A., Houlden H., Kirschner J., Schorling D., Rudnik-Schöneborn S., Strom TM., Leiz S., Juliette K., Richardson R., Yang Y., Zhang Y., Wang M., Wang J., Wang X., Platzer K., Donkervoort S., Bönnemann CG., Wagner M., Issa MY., Elbendary HM., Stanley V., Maroofian R., Gleeson JG., Zaki MS., Senderek J., Pandey UB.
GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.