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Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly
Nature genetics, 2017-10, Vol.49 (10), p.1529-1538
2017
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Autor(en) / Beteiligte
Titel
Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly
Ist Teil von
  • Nature genetics, 2017-10, Vol.49 (10), p.1529-1538
Ort / Verlag
New York: Nature Publishing Group US
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
  • Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt and colleagues report that mutations in OSGEP , TP53RK , TPRKB and LAGE3 , genes encoding KEOPS-complex subunits, cause Galloway–Mowat syndrome, a recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Functional studies suggest that the phenotypes result from impaired protein translation, thus leading to endoplasmic reticulum stress and apoptosis. Galloway–Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP , TP53RK , TPRKB , and LAGE3 , genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR–Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP , TP53RK , or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
Sprache
Englisch
Identifikatoren
ISSN: 1061-4036
eISSN: 1546-1718
DOI: 10.1038/ng.3933
Titel-ID: cdi_hal_primary_oai_HAL_hal_02187752v1
Format
–
Schlagworte
13/2, 13/89, 45/23, 45/47, 64/110, 64/116, 692/308/2056, 692/699/1585/2759/1523, 692/699/375/366, Actin, Agriculture, Animal Genetics and Genomics, Animals, Apoptosis, Apoptosis - genetics, Biomedicine, Biopsy, Brain, Cancer Research, Carrier Proteins - genetics, Cell Movement, Cell proliferation, CRISPR, CRISPR-Cas Systems, Cytoskeleton, Cytoskeleton - ultrastructure, Deoxyribonucleic acid, Development and progression, DNA, DNA damage, DNA Repair - genetics, Endoplasmic reticulum, Endoplasmic Reticulum Stress - genetics, Gene Function, Gene Knockout Techniques, Gene mutation, Genes, Genetic aspects, Genetic disorders, Genomes, Genotype & phenotype, Health aspects, Hernia, Hiatal - genetics, Human Genetics, Humans, Intracellular Signaling Peptides and Proteins - deficiency, Intracellular Signaling Peptides and Proteins - genetics, Kidney diseases, Kinases, Lethality, letter, Life Sciences, Mass spectrometry, Metalloendopeptidases - deficiency, Metalloendopeptidases - genetics, Mice, Microcephaly, Microcephaly - genetics, Microencephaly, Models, Molecular, Multiprotein Complexes - genetics, Mutation, Nephrosis - genetics, Nephrotic syndrome, Nephrotic Syndrome - genetics, Nephrotic Syndrome - pathology, Podocytes - metabolism, Podocytes - ultrastructure, Protein Conformation, Protein-Serine-Threonine Kinases - deficiency, Protein-Serine-Threonine Kinases - genetics, Proteins, RNA Processing, Post-Transcriptional - genetics, RNA, Transfer - metabolism, Scientific imaging, Telomere Homeostasis - genetics, Zebrafish, Zebrafish Proteins - deficiency, Zebrafish Proteins - genetics

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