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Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

(2017) NATURE GENETICS. 49(10). p.1529-1538
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Abstract
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.
Keywords
UNFOLDED PROTEIN RESPONSE, TRANSFER-RNA MODIFICATION, GALLOWAY-MOWAT SYNDROME, GENOME MAINTENANCE, MASS-SPECTROMETRY, SECKEL-SYNDROME, YEAST, DNA, KINASE, WDR73

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Chicago
Braun, Daniela A, Jia Rao, Geraldine Mollet, David Schapiro, Marie-Claire Daugeron, Weizhen Tan, Olivier Gribouval, et al. 2017. “Mutations in KEOPS-complex Genes Cause Nephrotic Syndrome with Primary Microcephaly.” Nature Genetics 49 (10): 1529–1538.
APA
Braun, D. A., Rao, J., Mollet, G., Schapiro, D., Daugeron, M.-C., Tan, W., Gribouval, O., et al. (2017). Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. NATURE GENETICS, 49(10), 1529–1538.
Vancouver
1.
Braun DA, Rao J, Mollet G, Schapiro D, Daugeron M-C, Tan W, et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. NATURE GENETICS. 2017;49(10):1529–38.
MLA
Braun, Daniela A, Jia Rao, Geraldine Mollet, et al. “Mutations in KEOPS-complex Genes Cause Nephrotic Syndrome with Primary Microcephaly.” NATURE GENETICS 49.10 (2017): 1529–1538. Print.
@article{8529653,
  abstract     = {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.},
  author       = {Braun, Daniela A and Rao, Jia and Mollet, Geraldine and Schapiro, David and Daugeron, Marie-Claire and Tan, Weizhen and Gribouval, Olivier and Boyer, Olivia and Revy, Patrick and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Lawson, Jennifer A and Schanze, Denny and Ashraf, Shazia and Ullmann, Jeremy F P and Hoogstraten, Charlotte A and Boddaert, Nathalie and Collinet, Bruno and Martin, Ga{\"e}lle and Liger, Dominique and Lovric, Svjetlana and Furlano, Monica and Guerrera, I Chiara and Sanchez-Ferras, Oraly and Hu, Jennifer F and Boschat, Anne-Claire and Sanquer, Sylvia and Menten, Bj{\"o}rn and Vergult, Sarah and De Rocker, Nina and Airik, Merlin and Hermle, Tobias and Shril, Shirlee and Widmeier, Eugen and Gee, Heon Yung and Choi, Won-Il and Sadowski, Carolin E and Pabst, Werner L and Warejko, Jillian K and Daga, Ankana and Basta, Tamara and Matejas, Verena and Scharmann, Karin and Kienast, Sandra D and Behnam, Babak and Beeson, Brendan and Begtrup, Amber and Bruce, Malcolm and Ch'ng, Gaik-Siew and Lin, Shuan-Pei and Chang, Jui-Hsing and Chen, Chao-Huei and Cho, Megan T and Gaffney, Patrick M and Gipson, Patrick E and Hsu, Chyong-Hsin and Kari, Jameela A and Ke, Yu-Yuan and Kiraly-Borri, Cathy and Lai, Wai-ming and Lemyre, Emmanuelle and Littlejohn, Rebecca Okashah and Masri, Amira and Moghtaderi, Mastaneh and Nakamura, Kazuyuki and Ozaltin, Fatih and Praet, Marleen and Prasad, Chitra and Prytula, Agnieszka and Roeder, Elizabeth R and Rump, Patrick and Schnur, Rhonda E and Shiihara, Takashi and Sinha, Manish D and Soliman, Neveen A and Soulami, Kenza and Sweetser, David A and Tsai, Wen-Hui and Tsai, Jeng-Daw and Topaloglu, Rezan and Vester, Udo and Viskochil, David H and Vatanavicharn, Nithiwat and Waxler, Jessica L and Wierenga, Klaas J and Wolf, Matthias T F and Wong, Sik-Nin and Leidel, Sebastian A and Truglio, Gessica and Dedon, Peter C and Poduri, Annapurna and Mane, Shrikant and Lifton, Richard P and Bouchard, Maxime and Kannu, Peter and Chitayat, David and Magen, Daniella and Callewaert, Bert and van Tilbeurgh, Herman and Zenker, Martin and Antignac, Corinne and Hildebrandt, Friedhelm},
  issn         = {1061-4036},
  journal      = {NATURE GENETICS},
  keyword      = {UNFOLDED PROTEIN RESPONSE,TRANSFER-RNA MODIFICATION,GALLOWAY-MOWAT SYNDROME,GENOME MAINTENANCE,MASS-SPECTROMETRY,SECKEL-SYNDROME,YEAST,DNA,KINASE,WDR73},
  language     = {eng},
  number       = {10},
  pages        = {1529--1538},
  title        = {Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly},
  url          = {http://dx.doi.org/10.1038/ng.3933},
  volume       = {49},
  year         = {2017},
}

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