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DOI 10.1038/s41467-021-22627-w

Медицинская библиотека · Nature communications · 2021

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.

Kour Sukhleen, Rajan Deepa S, Fortuna Tyler R, Anderson Eric N, Ward Caroline, Lee Youngha, Lee Sangmoon, Shin Yong Beom, Chae Jong-Hee, Choi Murim, Siquier Karine, Cantagrel Vincent, Amiel Jeanne, Stolerman Elliot S, Barnett Sarah S, Cousin Margot A, Castro Diana, McDonald Kimberly, Kirmse Brian, Nemeth Andrea H, Rajasundaram Dhivyaa, Innes A Micheil, Lynch Danielle, Frosk Patrick, Collins Abigail, Gibbons Melissa, Yang Michele, Desguerre Isabelle, Boddaert Nathalie, Gitiaux Cyril, Rydning Siri Lynne, Selmer Kaja K, Urreizti Roser, Garcia-Oguiza Alberto, Osorio Andrés Nascimento, Verdura Edgard, Pujol Aurora, McCurry Hannah R, Landers John E, Agnihotri Sameer, Andriescu E Corina, Moody Shade B, Phornphutkul Chanika, Sacoto Maria J Guillen, Begtrup Amber, Houlden Henry, Kirschner Janbernd, Schorling David, Rudnik-Schöneborn Sabine, Strom Tim M, Leiz Steffen, Juliette Kali, Richardson Randal, Yang Ying, Zhang Yuehua, Wang Minghui, Wang Jia, Wang Xiaodong, Platzer Konrad, Donkervoort Sandra, Bönnemann Carsten G, Wagner Matias, Issa Mahmoud Y, Elbendary Hasnaa M, Stanley Valentina, Maroofian Reza, Gleeson Joseph G, Zaki Maha S, Senderek Jan, Pandey Udai Bhan

СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: Kour Sukhleen, Rajan Deepa S, Fortuna Tyler R, Anderson Eric N, Ward Caroline, Lee Youngha, Lee Sangmoon, Shin Yong Beom, Chae Jong-Hee, Choi Murim, Siquier Karine, Cantagrel Vincent, Amiel Jeanne, Stolerman Elliot S, Barnett Sarah S, Cousin Margot A, Castro Diana, McDonald Kimberly, Kirmse Brian, Nemeth Andrea H, Rajasundaram Dhivyaa, Innes A Micheil, Lynch Danielle, Frosk Patrick, Collins Abigail, Gibbons Melissa, Yang Michele, Desguerre Isabelle, Boddaert Nathalie, Gitiaux Cyril, Rydning Siri Lynne, Selmer Kaja K, Urreizti Roser, Garcia-Oguiza Alberto, Osorio Andrés Nascimento, Verdura Edgard, Pujol Aurora, McCurry Hannah R, Landers John E, Agnihotri Sameer, Andriescu E Corina, Moody Shade B, Phornphutkul Chanika, Sacoto Maria J Guillen, Begtrup Amber, Houlden Henry, Kirschner Janbernd, Schorling David, Rudnik-Schöneborn Sabine, Strom Tim M, Leiz Steffen, Juliette Kali, Richardson Randal, Yang Ying, Zhang Yuehua, Wang Minghui, Wang Jia, Wang Xiaodong, Platzer Konrad, Donkervoort Sandra, Bönnemann Carsten G, Wagner Matias, Issa Mahmoud Y, Elbendary Hasnaa M, Stanley Valentina, Maroofian Reza, Gleeson Joseph G, Zaki Maha S, Senderek Jan, Pandey Udai Bhan. Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.. Nature communications. 2021. DOI: 10.1038/s41467-021-22627-w.

Предметные рубрики MeSH

AllelesAmino Acid SequenceAnimalsChild, PreschoolDevelopmental DisabilitiesDrosophilaFemaleGene Expression Regulation, DevelopmentalGene Knockdown TechniquesGene OntologyHEK293 CellsHumansInduced Pluripotent Stem CellsLoss of Function MutationMaleMuscle HypotoniaMyoclonic Cerebellar DyssynergiaNeurodevelopmental DisordersNeuronsPedigreePolymorphism, Single NucleotideRNA-SeqRibonucleoproteins, Small NuclearRigor MortisSMN Complex Proteins
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