Novel compound heterozygous mutation and phenotype in the tetratricopeptide repeat-like domain of the GEMIN5 gene in two Chinese families

Zhang, Xin; Guo, Yu; Xu, Lu; Wang, Yilong; Sheng, Guoxia; Gao, Feng; Yuan, Zhefeng

doi:10.1038/s10038-023-01184-8

J Hum Genet

2023

DOI: 10.1038/s10038-023-01184-8

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Novel compound heterozygous mutation and phenotype in the tetratricopeptide repeat-like domain of the GEMIN5 gene in two Chinese families

Xin Zhang

Yu Guo²,

Lu Xu

et al.

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2024

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Cited by 3 publications

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Oligomerization regulates the interaction of Gemin5 with members of the SMN complex and the translation machinery

Francisco-Velilla,

Abellan,

Embarc-Buh

et al. 2024

Cell Death Discov.

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RNA-binding proteins are multifunctional molecules impacting on multiple steps of gene regulation. Gemin5 was initially identified as a member of the survival of motor neurons (SMN) complex. The protein is organized in structural and functional domains, including a WD40 repeats domain at the N-terminal region, a tetratricopeptide repeat (TPR) dimerization module at the central region, and a non-canonical RNA-binding site at the C-terminal end. The TPR module allows the recruitment of the endogenous Gemin5 protein in living cells and the assembly of a dimer in vitro. However, the biological relevance of Gemin5 oligomerization is not known. Here we interrogated the Gemin5 interactome focusing on oligomerization-dependent or independent regions. We show that the interactors associated with oligomerization-proficient domains were primarily annotated to ribosome, splicing, translation regulation, SMN complex, and RNA stability. The presence of distinct Gemin5 protein regions in polysomes highlighted differences in translation regulation based on their oligomerization capacity. Furthermore, the association with native ribosomes and negative regulation of translation was strictly dependent on both the WD40 repeats domain and the TPR dimerization moiety, while binding with the majority of the interacting proteins, including SMN, Gemin2, and Gemin4, was determined by the dimerization module. The loss of oligomerization did not perturb the predominant cytoplasmic localization of Gemin5, reinforcing the cytoplasmic functions of this essential protein. Our work highlights a distinctive role of the Gemin5 domains for its functions in the interaction with members of the SMN complex, ribosome association, and RBP interactome.

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Oligomerization regulates the interaction of Gemin5 with members of the SMN complex and the translation machinery

Francisco-Velilla,

Abellan,

Embarc-Buh

et al. 2024

Cell Death Discov.

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Alternative splicing events driven by altered levels of GEMIN5 undergo translation

Francisco-Velilla,

Abellan,

Garcia-Martin

et al. 2024

RNA Biology

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Function and dysfunction of GEMIN5: understanding a novel neurodevelopmental disorder

Nelson,

Pandey

2024

Neural Regeneration Research

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The recent identification of a neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) has resulted in an increased interest in GEMIN5, a multifunction RNA-binding protein. As the largest member of the survival motor neuron complex, GEMIN5 plays a key role in the biogenesis of small nuclear ribonucleoproteins while also exhibiting translational regulatory functions as an independent protein. Although many questions remain regarding both the pathogenesis and pathophysiology of this new disorder, considerable progress has been made in the brief time since its discovery. In this review, we examine GEMIN5 within the context of NEDCAM, focusing on the structure, function, and expression of the protein specifically in regard to the disorder itself. Additionally, we explore the current animal models of NEDCAM, as well as potential molecular pathways for treatment and future directions of study. This review provides a comprehensive overview of recent advances in our understanding of this unique member of the survival motor neuron complex.

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Novel compound heterozygous mutation and phenotype in the tetratricopeptide repeat-like domain of the GEMIN5 gene in two Chinese families

Cited by 3 publications

References 20 publications

Oligomerization regulates the interaction of Gemin5 with members of the SMN complex and the translation machinery

Oligomerization regulates the interaction of Gemin5 with members of the SMN complex and the translation machinery

Alternative splicing events driven by altered levels of GEMIN5 undergo translation

Function and dysfunction of GEMIN5: understanding a novel neurodevelopmental disorder

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