Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.

TitleLoss of function mutations in GEMIN5 cause a neurodevelopmental disorder.
Publication TypeJournal Article
Year of Publication2021
AuthorsKour, S, Rajan, DS, Fortuna, TR, Anderson, EN, Ward, C, Lee, Y, Lee, S, Shin, YBeom, 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, A Innes, M, Lynch, D, Frosk, P, Collins, A, Gibbons, M, Yang, M, Desguerre, I, Boddaert, N, Gitiaux, C, Rydning, SLynne, Selmer, KK, Urreizti, R, Garcia-Oguiza, A, Osorio, ANascimento, Verdura, E, Pujol, A, McCurry, HR, Landers, JE, Agnihotri, S, E Andriescu, C, Moody, SB, Phornphutkul, C, Sacoto, MJGuillen, 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, MAHS, Senderek, J, Pandey, UBhan
JournalNat Commun
Date Published2021 05 07
KeywordsAlleles, Amino Acid Sequence, Animals, Child, Preschool, Developmental Disabilities, Drosophila, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Ontology, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Muscle Hypotonia, Myoclonic Cerebellar Dyssynergia, Neurodevelopmental Disorders, Neurons, Pedigree, Polymorphism, Single Nucleotide, Ribonucleoproteins, Small Nuclear, Rigor Mortis, RNA-Seq, SMN Complex Proteins

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.

Alternate JournalNat Commun
PubMed ID33963192
PubMed Central IDPMC8105379
Grant ListR01 NS073873 / NS / NINDS NIH HHS / United States
R01 NS098004 / NS / NINDS NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
U54 HD090256 / HD / NICHD NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States