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

Abstract

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.

Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

“…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.…”

“…The mutant R1016C in the individual of case 1 is found in compound heterozygosity with a 5′ splice variant in intron 4 that is predicted to produce a truncated protein, suggesting that the R1016C mutation individually is crucial for the activity of Gemin5 in the cellular environment. In addition, the R1016C mutation has been detected in unrelated patients ( Rajan et al, 2022 ), supporting an overall negative effect in protein function. Thus, the observed destabilizing effect of mutant D1019E in vitro, together with the negative effects of R1016C in living cells, strongly suggest that substitutions in the loop α12-13 of the TPR-like moiety have a negative impact on protein dimerization.…”

“…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.…”

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

“…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 ].…”

Phosphorylation of T897 in the dimerization domain of Gemin5 modulates protein interactions and translation regulation

“…Gemin5 biallelic variants were recently linked with human neurodevelopmental disorders, perturbing distinct pathways as compared to defects in the SMN protein causing spinal muscular atrophy (SMA) [22] , [23] , [24] , [25] . Dimerization defects in Gemin5 variants described in patients with neurological disorders resulted in the loss of factors connected to RNA processing, translation regulation, and spliceosome assembly [25] , establishing a link between the pathogenic mutations and protein malfunction.…”