Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms

TA Forbes; SE Howden; K Lawlor; B Phipson; J Maksimovic; L Hale; S Wilson; C Quinlan; G Ho; K Holman; B Bennetts; J Crawford; P Trnka; A Oshlack; C Patel; A Mallett; C Simons; MH Little

Journal article

Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms

TA Forbes, SE Howden, K Lawlor, B Phipson, J Maksimovic, L Hale, S Wilson, C Quinlan, G Ho, K Holman, B Bennetts, J Crawford, P Trnka, A Oshlack, C Patel, A Mallett, C Simons, MH Little

American Journal of Human Genetics | CELL PRESS | Published : 2018

DOI: 10.1016/j.ajhg.2018.03.014

Abstract

Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. IFT140 plays a key role in retrogr..

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University of Melbourne Researchers

Belinda Phipson Author

Jovana Maksimovic Author

Catherine Quinlan Author

Alicia Oshlack Author

Grants

Awarded by Murdoch Children's Research Institute

Funding Acknowledgements

We thank Pei Xuan Er and Irene Ghobrial for assistance with iPSC derivation and maintenance, Alison Graham for iPSC pluripotency flow cytometry, and Andrew Lonsdale for assistance with bioinformatic graphical outputs. This study was funded by the National Health and Medical Research Council of Australia (NHMRC) (GNT1098654), Kidney Health Australia, the Royal Brisbane and Women's Hospital Foundation, the Royal Children's Hospital Foundation, and the Murdoch Children's Research Institute. The Murdoch Childrens Research Institute is supported by the Victorian Government's Operational Infrastructure Support Program. T.A.F. is a recipient of the NHMRC Postgraduate Scholarship (GNT1114409) and RACP Jacquot Award. M.H.L. is an NHMRC Senior Principal Research Fellow and has consulted for and received research funding from Organovo Inc.