Pathogenic variants in the survival of motor neurons complex gene <scp><i>GEMIN5</i></scp> cause cerebellar atrophy

Saida, Ken; Tamaoki, Junya; Sasaki, Masayuki; Haniffa, Muzhirah; Koshimizu, Eriko; Sengoku, Toru; Maeda, Hiroki; Kikuchi, Masahiro; Yokoyama, Haruna; Sakamoto, Masamune; Iwama, Kazuhiro; Sekiguchi, Futoshi; Hamanaka, Kohei; Fujita, Atsushi; Mizuguchi, Takeshi; Ogata, Kazuhiro; Miyake, Noriko; Miyatake, Satoko; Matsumoto, Naomichi

doi:10.1111/cge.14066

Cited by 20 publications

(20 citation statements)

References 22 publications

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“…The presence of Gemin5 variants clustered in conserved residues of the dimerization domain, which provides a platform for protein–protein/RNA interactions ( Moreno-Morcillo et al, 2020 ), reinforces the biological relevance of the TPR-like module for Gemin5 function. Fully consistent with this hypothesis, Gemin5 biallelic variants have been recently associated with cerebellar atrophy and spastic ataxia in several human patients ( Saida et al, 2021 ; Rajan et al, 2022 ). The phenotypic differences observed among individuals carrying similar but nonidentical substitutions in Gemin5 protein remain to be understood as the number of patients affected by this novel disease increase.…”

Section: Discussionsupporting

confidence: 55%

“…We show in this study that Gemin5 pathogenic variants mapping in the protein dimerization module (TPR-like) and the noncanonical RNA-binding domain (RBS1) impair the function of this multitasking protein in central cellular processes, including ribosome binding, translation regulation, and protein–protein association. Of note, the clinical disorders associated with these Gemin5 variants differ from those linked to SMN protein dysfunction ( Kour et al, 2021 ; Saida et al, 2021 ). Consequently, these results lead us to propose that variants causing Gemin5 failure result in protein malfunction and, hence, are at the basis of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Gemin5 has been identified as a member of RNP networks associated to distinct cytoplasmic aggregates ( Jiang et al, 2018 ; Vu et al, 2021 ; Wollen et al, 2021 ). More importantly, Gemin5 variants were recently linked with human neurodevelopmental disorders, perturbing distinct pathways as compared with defects in the SMN protein ( Kour et al, 2021 ; Saida et al, 2021 ; Rajan et al, 2022 ). However, the molecular basis of Gemin5 dysfunction remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

et al. 2022

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Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)–like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protein.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

et al. 2022

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“…GEMIN5 is expressed predominantly in the cytoplasm as well as in the nucleus, nucleoplasm, and gem bodies, suggesting functions in multiple cellular compartments ( Pacheco et al, 2009 ; Piñeiro et al, 2015 ; Francisco-Velilla et al, 2016 ; Lozano et al, 2018 ; Martinez-Salas et al, 2020 ; Moreno-Morcillo et al, 2020 ). Animal model studies suggest that complete or partial reduction of the snRNP complex proteins are detrimental ( Saida et al, 2021 ). Knocking out Smn , Gemin4 , and Gemin5 is lethal in mice and Drosophila , suggesting that these proteins are essential for survival ( Gates et al, 2004 ; Gavrilina et al, 2008 ; Meier et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5

Rajan

Kour

Fortuna

et al. 2022

Front. Cell Dev. Biol.

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The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.

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“…Consistent with this notion, this protein participates in various cellular processes, including tissue regeneration [ 7 ], recognition of 7S RNA Signal Recognition Particle (SRP) [ 8 ], trans-splicing [ 9 ], and translation control [ 10 ]. In further support of the critical activities of this ubiquitously expressed protein for cell growth, recent studies showed that human Gemin5 variants cause developmental disorders presumably due to decreased levels of endogenous Gemin5 protein [ 11 – 14 ], summing up to the observation that a null KO mouse is embryonic lethal [ 12 ], as well as in zebrafish and Drosophila [ 13 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Gemin5-dependent RNA association with polysomes enables selective translation of ribosomal and histone mRNAs

Embarc-Buh

Francisco‐Velilla

García-Martín

et al. 2022

Cell. Mol. Life Sci.

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Selective translation allows to orchestrate the expression of specific proteins in response to different signals through the concerted action of cis-acting elements and RNA-binding proteins (RBPs). Gemin5 is a ubiquitous RBP involved in snRNP assembly. In addition, Gemin5 regulates translation of different mRNAs through apparently opposite mechanisms of action. Here, we investigated the differential function of Gemin5 in translation by identifying at a genome-wide scale the mRNAs associated with polysomes. Among the mRNAs showing Gemin5-dependent enrichment in polysomal fractions, we identified a selective enhancement of specific transcripts. Comparison of the targets previously identified by CLIP methodologies with the polysome-associated transcripts revealed that only a fraction of the targets was enriched in polysomes. Two different subsets of these mRNAs carry unique cis-acting regulatory elements, the 5’ terminal oligopyrimidine tracts (5’TOP) and the histone stem-loop (hSL) structure at the 3’ end, respectively, encoding ribosomal proteins and histones. RNA-immunoprecipitation (RIP) showed that ribosomal and histone mRNAs coprecipitate with Gemin5. Furthermore, disruption of the TOP motif impaired Gemin5-RNA interaction, and functional analysis showed that Gemin5 stimulates translation of mRNA reporters bearing an intact TOP motif. Likewise, Gemin5 enhanced hSL-dependent mRNA translation. Thus, Gemin5 promotes polysome association of only a subset of its targets, and as a consequence, it favors translation of the ribosomal and the histone mRNAs. Together, the results presented here unveil Gemin5 as a novel translation regulator of mRNA subsets encoding proteins involved in fundamental cellular processes.

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Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy

Cited by 20 publications

References 22 publications

Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5

Gemin5-dependent RNA association with polysomes enables selective translation of ribosomal and histone mRNAs

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