Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.

Nature Communications
Sukhleen KourUdai Bhan Pandey

Abstract

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.

References

Jun 25, 1996·Proceedings of the National Academy of Sciences of the United States of America·S C LiC M Deber
May 10, 2001·Current Opinion in Cell Biology·C L Will, R Lührmann
Nov 21, 2001·The Journal of Biological Chemistry·Amelie K GubitzGideon Dreyfuss
May 8, 2002·Nature Reviews. Molecular Cell Biology·Gideon DreyfussNaoyuki Kataoka
Jul 2, 2002·Proceedings of the National Academy of Sciences of the United States of America·Sibylle JablonkaMichael Sendtner
Dec 3, 2002·Science·Livio PellizzoniGideon Dreyfuss
Jun 26, 2003·Nucleic Acids Research·Pauline C Ng, Steven Henikoff
May 28, 2005·Experimental Gerontology·Julia Warner GarganoMichael S Grotewiel
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Nov 30, 2005·Molecular and Cellular Biology·Tracey J GolembeGideon Dreyfuss
Jul 22, 2006·Molecular Cell·Daniel J BattleGideon Dreyfuss
Dec 21, 2006·The Journal of Biological Chemistry·Simon OtterUtz Fischer
Feb 20, 2007·The Journal of Biological Chemistry·Chihiro OgawaHarukazu Suzuki
Mar 27, 2007·Cold Spring Harbor Symposia on Quantitative Biology·D J BattleG Dreyfuss
May 29, 2007·Nucleic Acids Research·Yana Bromberg, Burkhard Rost
Jul 21, 2007·The Journal of Biological Chemistry·Daniel J BattleGideon Dreyfuss
Mar 18, 2008·FEBS Letters·Tina GlisovicGideon Dreyfuss
Dec 11, 2008·Nucleic Acids Research·Almudena PachecoEncarnación Martínez-Salas
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Apr 21, 2009·Nature Structural & Molecular Biology·Chi-kong LauGideon Dreyfuss
Jul 9, 2009·Nature Reviews. Neuroscience·Arthur H M Burghes, Christine E Beattie
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
May 11, 2010·Experimental Cell Research·Ruben J CauchiJi-Long Liu
Jun 2, 2010·Molecular Cell·Jeongsik YongGideon Dreyfuss
Jul 14, 2011·Orphanet Journal of Rare Diseases·Yasmin NamavarFrank Baas
Mar 22, 2012·Journal of Visualized Experiments : JoVE·Charles D NicholsUdai B Pandey
Jun 5, 2012·Cell·Alfredo CastelloMatthias W Hentze
Jun 12, 2012·Molecular Cell·Alexander G BaltzMarkus Landthaler
Oct 12, 2012·PloS One·Yongwook ChoiAgnes P Chan
Dec 12, 2012·Nucleic Acids Research·Nathalie PiazzonSéverine Massenet
Dec 12, 2012·Nucleic Acids Research·David PiñeiroEncarnación Martínez-Salas
Jan 4, 2013·Neurology·Sabine Rudnik-SchönebornKlaus Zerres
Feb 19, 2013·Trends in Genetics : TIG·Alfredo CastelloThomas Preiss
Mar 13, 2013·Nature Reviews. Genetics·Michaela Müller-McNicoll, Karla M Neugebauer
Aug 3, 2013·Nucleic Acids Research·Luhan YangGeorge Church
Dec 18, 2013·Science·Ophir ShalemFeng Zhang
Mar 7, 2014·Nucleic Acids Research·Javier Fernandez-ChamorroEncarnación Martinez-Salas
Jun 3, 2014·Orphanet Journal of Rare Diseases·Iciar Sánchez-AlbisuaIngeborg Krägeloh-Mann
Jul 31, 2014·Nature Methods·Neville E SanjanaFeng Zhang

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Citations

Aug 17, 2021·Frontiers in Molecular Biosciences·Elisabeth LataMartin Teichmann

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Software Mentioned

PhD
muPRO
R package
Provean
Database for Annotation , Visualization and Integrated Discove...
GeneMatcher
RSEM
Bowtie2
GnomAD
SIFT

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