. 2021 May 7;12(1):2558.

doi: 10.1038/s41467-021-22627-w.

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Sukhleen Kour^#¹, Deepa S Rajan^#¹, Tyler R Fortuna¹, Eric N Anderson¹, Caroline Ward¹, Youngha Lee², Sangmoon Lee², Yong Beom Shin³, Jong-Hee Chae⁴, Murim Choi^{2

4}, Karine Siquier⁵, Vincent Cantagrel⁵, Jeanne Amiel⁶, Elliot S Stolerman⁷, Sarah S Barnett⁸, Margot A Cousin⁹, Diana Castro¹⁰, Kimberly McDonald¹¹, Brian Kirmse¹², Andrea H Nemeth^{13

14}, Dhivyaa Rajasundaram¹⁵, A Micheil Innes¹⁶, Danielle Lynch¹⁶, Patrick Frosk¹⁷, Abigail Collins¹⁸, Melissa Gibbons¹⁸, Michele Yang¹⁸, Isabelle Desguerre¹⁹, Nathalie Boddaert²⁰, Cyril Gitiaux²¹, Siri Lynne Rydning²², Kaja K Selmer²³, Roser Urreizti²⁴, Alberto Garcia-Oguiza²⁵, Andrés Nascimento Osorio²⁶, Edgard Verdura²⁷, Aurora Pujol^{27

28}, Hannah R McCurry²⁹, John E Landers³⁰, Sameer Agnihotri³¹, E Corina Andriescu³², Shade B Moody³², Chanika Phornphutkul³³, Maria J Guillen Sacoto³⁴, Amber Begtrup³⁴, Henry Houlden³⁵, Janbernd Kirschner³⁶, David Schorling³⁶, Sabine Rudnik-Schöneborn³⁷, Tim M Strom³⁸, Steffen Leiz³⁹, Kali Juliette⁴⁰, Randal Richardson⁴⁰, Ying Yang⁴¹, Yuehua Zhang⁴¹, Minghui Wang⁴², Jia Wang⁴³, Xiaodong Wang⁴³, Konrad Platzer⁴⁴, Sandra Donkervoort⁴⁵, Carsten G Bönnemann⁴⁵, Matias Wagner⁴⁶, Mahmoud Y Issa⁴⁷, Hasnaa M Elbendary⁴⁷, Valentina Stanley⁴⁸, Reza Maroofian³⁵, Joseph G Gleeson⁴⁸, Maha S Zaki⁴⁷, Jan Senderek⁴⁹, Udai Bhan Pandey^{50

51

52}

Affiliations

¹ Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
² Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
³ Department of Rehabilitative Medicine, Pusan National University School of Medicine, Pusan, Republic of Korea.
⁴ Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁵ Developmental Brain Disorders Laboratory, Paris University, Imagine Institute, INSERM UMR, Paris, France.
⁶ Department of Genetics, AP-HP, Necker Enfants Malades Hospital, Paris University, Imagine Institute, Paris, France.
⁷ Greenwood Genetic Center, Greenwood, SC, USA.
⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁹ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹¹ University of Mississippi Medical Center, Jackson, MS, USA.
¹² Division of Genetics, University of Mississippi Medical Center, Jackson, MS, USA.
¹³ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹⁴ Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK.
¹⁵ Department of Pediatrics, Division of Health Informatics, Childrens Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
¹⁷ Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
¹⁸ Department of Pediatrics and Neurology, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁹ Department of Pediatric Neurology, AP-HP, Necker Enfants Malades Hospital, Paris University Imagine Institute, Paris, France.
²⁰ Department of Pediatric Radiology, AP-HP, Necker Enfants Malades Hospital, Paris University Imagine Institute, Paris, France.
²¹ Department of Pediatric Neurophysiology AP-HP, Necker Enfants Malades Hospital, Paris University, Paris, France.
²² Department of Neurology, Oslo University Hospital, Oslo, Norway.
²³ Department of Research and Development, Division of Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway.
²⁴ Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu and CIBERER, Barcelona, Spain.
²⁵ Hospital Universitario Miguel Servet, Zaragoza, Spain.
²⁶ Hospital Sant Joan de Déu, Barcelona, Spain.
²⁷ Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
²⁸ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
²⁹ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁰ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
³¹ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³² Department of Pediatrics, University of Texas Health Science Center, Houston, TX, USA.
³³ Department of Pediatrics, Division of Human Genetics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.
³⁴ GeneDx, Gaithersburg, MD, USA.
³⁵ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
³⁶ Department of Neuropediatrics and Muscle Disorders, Medical Center,, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁷ Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
³⁸ Institute of Human Genetics, Faculty of Medicine, Technical University Munich, Munich, Germany.
³⁹ Clinic for Children and Adolescents Dritter Orden, Divison of Neuropediatrics, Munchen, Germany.
⁴⁰ Department of Neurology, Gillette Children's Specialty Healthcare, St Paul, MN, USA.
⁴¹ Department of Pediatrics, Peking University First Hospital, Beijing, China.
⁴² The First People's Hospital of Changde City, Hunan, China.
⁴³ Cipher Gene Ltd, Beijing, China.
⁴⁴ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁴⁵ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴⁶ Institute of Human Genetics, Klinikum rechts der IsarTechnical, University of Munich, Munich, Germany.
⁴⁷ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
⁴⁸ Departments of Neurosciences and Pediatrics, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.
⁴⁹ Department of Neurology, Friedrich-Baur-Institute, University Hospital, LMU Munich, Munich, Germany.
⁵⁰ Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. udai@pitt.edu.
⁵¹ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. udai@pitt.edu.
⁵² Children's Neuroscience Institute, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. udai@pitt.edu.

^# Contributed equally.

PMID: 33963192
PMCID: PMC8105379
DOI: 10.1038/s41467-021-22627-w

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Sukhleen Kour et al. Nat Commun. 2021.

. 2021 May 7;12(1):2558.

doi: 10.1038/s41467-021-22627-w.

Authors

Affiliations

¹ Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
² Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
³ Department of Rehabilitative Medicine, Pusan National University School of Medicine, Pusan, Republic of Korea.
⁴ Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁵ Developmental Brain Disorders Laboratory, Paris University, Imagine Institute, INSERM UMR, Paris, France.
⁶ Department of Genetics, AP-HP, Necker Enfants Malades Hospital, Paris University, Imagine Institute, Paris, France.
⁷ Greenwood Genetic Center, Greenwood, SC, USA.
⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁹ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹¹ University of Mississippi Medical Center, Jackson, MS, USA.
¹² Division of Genetics, University of Mississippi Medical Center, Jackson, MS, USA.
¹³ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹⁴ Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK.
¹⁵ Department of Pediatrics, Division of Health Informatics, Childrens Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
¹⁷ Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
¹⁸ Department of Pediatrics and Neurology, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁹ Department of Pediatric Neurology, AP-HP, Necker Enfants Malades Hospital, Paris University Imagine Institute, Paris, France.
²⁰ Department of Pediatric Radiology, AP-HP, Necker Enfants Malades Hospital, Paris University Imagine Institute, Paris, France.
²¹ Department of Pediatric Neurophysiology AP-HP, Necker Enfants Malades Hospital, Paris University, Paris, France.
²² Department of Neurology, Oslo University Hospital, Oslo, Norway.
²³ Department of Research and Development, Division of Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway.
²⁴ Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu and CIBERER, Barcelona, Spain.
²⁵ Hospital Universitario Miguel Servet, Zaragoza, Spain.
²⁶ Hospital Sant Joan de Déu, Barcelona, Spain.
²⁷ Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
²⁸ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
²⁹ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁰ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
³¹ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³² Department of Pediatrics, University of Texas Health Science Center, Houston, TX, USA.
³³ Department of Pediatrics, Division of Human Genetics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.
³⁴ GeneDx, Gaithersburg, MD, USA.
³⁵ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
³⁶ Department of Neuropediatrics and Muscle Disorders, Medical Center,, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁷ Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
³⁸ Institute of Human Genetics, Faculty of Medicine, Technical University Munich, Munich, Germany.
³⁹ Clinic for Children and Adolescents Dritter Orden, Divison of Neuropediatrics, Munchen, Germany.
⁴⁰ Department of Neurology, Gillette Children's Specialty Healthcare, St Paul, MN, USA.
⁴¹ Department of Pediatrics, Peking University First Hospital, Beijing, China.
⁴² The First People's Hospital of Changde City, Hunan, China.
⁴³ Cipher Gene Ltd, Beijing, China.
⁴⁴ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁴⁵ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴⁶ Institute of Human Genetics, Klinikum rechts der IsarTechnical, University of Munich, Munich, Germany.
⁴⁷ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
⁴⁸ Departments of Neurosciences and Pediatrics, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.
⁴⁹ Department of Neurology, Friedrich-Baur-Institute, University Hospital, LMU Munich, Munich, Germany.
⁵⁰ Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. udai@pitt.edu.
⁵¹ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. udai@pitt.edu.
⁵² Children's Neuroscience Institute, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. udai@pitt.edu.

^# Contributed equally.

PMID: 33963192
PMCID: PMC8105379
DOI: 10.1038/s41467-021-22627-w

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.

PubMed Disclaimer

Conflict of interest statement

J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics. J.E.L. is a consultant and may provide expert testimony for Perkins Coie LLP. All other authors declare no competing interests.

Figures

**Fig. 1. Variants in *GEMIN5* cause developmental delay, hypotonia, motor dysfunction, and cerebellar atrophy.**
a Pedigree of the patients with homozygous variants in *GEMIN5*. Affected individuals who underwent clinical examinations are represented by arrowhead. b Multiple sequence alignment showing conservation of amino acid residues in GEMIN5 (red rectangle) across species. Polyphen-2 analysis predicted probably damaging effect of variants on GEMIN5 structure and function. c Schematic showing functional domains and position of homozygous variants in GEMIN5 protein. d–j MRI scans showing characteristic cerebellar atrophy (white arrow) in patients carrying different bi-allelic variants in *GEMIN5* (+ represents wild type allele of GEMIN5).

**Fig. 2. Differential subcellular expression of SMN assembly proteins in iPSC-derived neuronal cells carrying His913Arg and Leu1068Pro GEMIN5 variants.**
a Representative Immunofluorescence (IF) images showing the sub-cellular mislocalization of GEMIN5 in IPSCs derived neuronal cells carrying p. His913Arg and p. Leu1068Pro hetero- and homozygous variants. H913R/H913R^A6 and H913R/H913R^A11 were the two isogenic iPSC clones for H913R homozygous variant used in the study (scale bar = 10 µm). b, c Quantitative analysis displaying the changes in nuclear (b) cytoplasmic (c) distribution pattern of GEMIN5 as in (a), measured as integrated density values (IDV) in H913R hetero and homozygous neuronal cells (one-way ANOVA- Bonferroni test, n = 30–40). d, e Quantitative analysis showing the nuclear (d) cytoplasmic (e) distribution of GEMIN5 as in (a) in L1068P hetero and homozygous neuronal cells (two tailed Mann–Whitney U test, n = 25–30). f Representative IF images showing the differential subcellular pattern of GEMIN2 in IPSCs-derived H913R and L1068P neuronal cells (scale bar = 10 µm). g–j Quantitative bar plot representing the integrated density values of GEMIN2 in the nucleus (g, i) and cytoplasm (h, j) of H913R (g, h) and L1068P (i, j) GEMIN5 neuronal cell soma (two tailed Mann–Whitney U test, n ≥ 25). The data are represented as mean ± SEM. P values (****<0.0001, ***<0.001, **<0.01) are of unpaired Student’s t test. Source data are provided as a Source Data file.

**Fig. 3. GEMIN5 variants reduce the levels of GEMIN5 and SMN assembly proteins.**
a Western blot (WB) analysis of total protein extract from IPSC-derived neuronal cells carrying mono-allelic and bi-allelic L1068P *GEMIN5* variants depicting the levels of GEMIN5, GEMIN4, GEMIN6, and GEMIN2, SMN, and U1A, respectively. b Quantitative bar plots showing the reduced levels of GEMIN5 and SMN assembly proteins in L1068P homozygous neurons compared to heterozygous controls (two-tailed unpaired t test, n = 4). c Representative WB depicting the expression levels of GEMIN5 and SMN complex proteins in heterozygous and homozygous H913R neurons d–j, Quantitative comparison of expression levels of GEMIN5 (d), GEMIN4 (e), SMN (f), GEMIN6 (g), GEMIN2 (h), U1A (i), and GEMIN3 (j) between H913R^−/− and H913R^+/− neuronal cells as in (d) (one-way ANOVA-Bonferroni test, n = 4). k, l Representative WB showing the protein levels of GEMIN5, GEMIN4, and SMN in L1068P heterozygous (k) and homozygous (l) neurons after 0, 2, 4, 8, 12, and 24 h of cycloheximide (CHX) treatment. Tubulin was used as normalization control. m–o Quantitative analysis of the rate of degradation of GEMIN5 (m), SMN (n), and GEMIN4 (o) after CHX treatment showed the increased rate of depletion of GEMIN5 and SMN in homozygous L1068P neurons as compared to heterozygous controls (nonlinear regression-one phase decay, n = 4). p, q Expression analysis of GEMIN5, SMN, and other GEM-proteins by qPCR in L1068P (p) and H913R (q) neurons. The transcript levels of GEMIN5, GEMIN4, GEMIN3, GEMIN6, GEMIN2, and SMN showed no significant changes among heterozygous and homozygous GEMIN5, L1068P, and H193R variants (two tailed Mann–Whitney U test, n = 6). r Quantitative PCR showing the relative stability of GEMIN5 mRNA between hetero and homozygous L1068P neurons by using total RNA isolated at 0, 1, 2, 4, 6, and 8 h after actinomycin D treatment (nonlinear regression-one phase decay, n = 4). The data represent mean ± SEM. P values (****<0.0001, ***<0.001, **<0.01). Source data are provided as a Source Data file.

**Fig. 4. Loss of GEMIN5 leads to decrease levels of snRNP complex proteins and, developmental defects and motor dysfunction in *Drosophila*.**
a Representative WB showing the effect of shRNA-mediated knockdown of GEMIN5 on the levels of GEMIN4, GEMIN3, GEMIN2, GEMIN6, SMN, SmB1/B2, and U1A as compared to scrambled control. GEMIN5 shRNA B was used in combination with GEMIN5 shRNA 5 and 4 to obtain the maximum knockdown efficiency. α tubulin was used as internal control (n = 5). b–I Quantitative analysis showed a significant decrease in the levels of GEMIN4 (c), GEMIN3 (d), GEMIN6 (e), SMN (f), GEMIN2 (g), and SmB1/B2 (h) upon ~65% knockdown of GEMIN5 (b). No significant change was found in U1A protein levels (i) (one-way ANOVA-Bonferroni test, n = 5). j Flow diagram comparing different developmental stages of flies between *rigor mortis* RNAi and W1118 control flies. RNAi-mediated knockdown of *rigor mortis*, as determined by qPCR in (k), resulted in pupal lethality (j) and eclosion defects (l) as measured by percentage eclosed adult homozygous flies (two tailed unpaired t test, n = 5). The RNAi transgene under inducible tubulin-UAS gal4 system was expressed by growing the larvae on 1 mM RU486 drug food. m Representative IF images of neuromuscular junction (NMJ) marked with HRP (pre-synaptic marker) in the larval segment expressing *rig mortis* RNAi compared to control (scale bar = 10 µm). n Quantitative comparison of the bouton size measured as area per NMJ between the rig mortis RNAi expressing larvae and control (two-tailed Mann–Whitney U test, n = 12). o Bar graph representing rapid iterative negative geotaxis (RING) assay, calculated as climbing speed of a fly per second, showed significant defects in the climbing velocities of flies with RNAi-mediated GEMIN5 KD as compared to controls. The effect was apparent when the transgene was expressed for 20 days on 20 mM RU486 drug food under the control of tubulin-GS driver (two-tailed Mann–Whitney U test, n = 25–39). p Kaplan–Meier survival plot showing the effect of the loss of endogenous *rig mortis* on the life span of flies. The flies were grown on 20 mM RU486 drug food to express the *rig mortis* RNAi transgene and monitored every day for the span of 45 days (log-rank (Mantel–Cox) test, n = 80). The data represent mean ± SEM. P values (****<0.0001, ***<0.001, **<0.01). Source data are provided as a Source Data file.

**Fig. 5. Biallelic variants in *GEMIN5* disrupts SMN assembly formation in vitro.**
a Representative gel image showing the in vitro snRNP assembly formation by using 3′ Cy3-biotin-labeled U1 snRNA and the cytoplasmic extract from heterozygous and homozygous L1068P and H913R neurons as well as from the HEK293T cells transfected with GEMIN5 shRNA. b Quantitative analysis of the in vitro SMN complex formation as given in (a) (one-way ANOVA-Bonferroni test, n = 3)**. c** Immunoprecipitation blot showing the reduced interaction of HA-tagged Leu1068Pro and His913Arg variants with GEMIN4, GEMIN3, and SMN as compared to HA-GEMIN5 WT protein in HEK cells. d Diagrammatic representation showing the possible mode of disruption in snRNP complex formation due to loss of GEMIN5 in L1068P and H913R variants. P-values ***<0.01, **<0.05. Source data are provided as a Source Data file.

**Fig. 6. RNA-seq analysis of GEMIN5 patient iPSC neurons reveals a distinct and unique transcriptomic profile compared to SMA patient iPSC neurons.**
a, b Volcano plot showing up and down-regulated genes in SMN^Exon7del vs. control (a) and, GEMIN5^H913R vs. control (b) selected by p-value < 0.01 & log2(fold change) ≥ 1.5. The x-axes show log2 values of the fold changes in gene expression between the samples and y-axis shows −log10-transformed p-values. Significant genes were selected after Benjamini–Hochberg (BH) correction. c Venn diagram showing the number of genes that are shared between SMA and GEMIN5 and the genes which are exclusively to both. Only the DEGs with ≥1.5 log-fold DEGs were used for the comparison. d Heat map depicting the expression pattern of top 20 up and downregulated DEGs common to both SMN^Exon7del and GEMIN5^H913R. Significant genes were selected by Wald test in DESeq2 and multiple test correction by BH. e–g Functional characterization of the genes with the MSigDB ‘c5 Gene Ontology (GO), biological process ontology (BP) v6.0’ gene sets in SMN^Exon7del and GEMIN5^H913R (e), unique to GEMIN5^H913R (f) and SMN^Exon7del (g). The size of the dot corresponds to the number of genes per term, and the color of the dot indicates the enrichment significance. Source data are provided as a Source Data file.

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Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

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Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Authors

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Conflict of interest statement

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