De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Item Type:	Article
Title:	De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis
Creators Name:	Weng, P.L. and Majmundar, A.J. and Khan, K. and Lim, T.Y. and Shril, S. and Jin, G. and Musgrove, J. and Wang, M. and Ahram, D.F. and Aggarwal, V.S. and Bier, L.E. and Heinzen, E.L. and Onuchic-Whitford, A.C. and Mann, N. and Buerger, F. and Schneider, R. and Deutsch, K. and Kitzler, T.M. and Klämbt, V. and Kolb, A. and Mao, Y. and Moufawad El Achkar, C. and Mitrotti, A. and Martino, J. and Beck, B.B. and Altmüller, J. and Benz, M.R. and Yano, S. and Mikati, M.A. and Gunduz, T. and Cope, H. and Shashi, V. and Trachtman, H. and Bodria, M. and Caridi, G. and Pisani, I. and Fiaccadori, E. and AbuMaziad, A.S. and Martinez-Agosto, J.A. and Yadin, O. and Zuckerman, J. and Kim, A. and John-Kroegel, U. and Tyndall, A.V. and Parboosingh, J.S. and Innes, A.M. and Bierzynska, A. and Koziell, A.B. and Muorah, M. and Saleem, M.A. and Hoefele, J. and Riedhammer, K.M. and Gharavi, A.G. and Jobanputra, V. and Pierce-Hoffman, E. and Seaby, E.G. and O'Donnell-Luria, A. and Rehm, H.L. and Mane, S. and D'Agati, V.D. and Pollak, M.R. and Ghiggeri, G.M. and Lifton, R.P. and Goldstein, D.B. and Davis, E.E. and Hildebrandt, F. and Sanna-Cherchi, S.
Abstract:	Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
Keywords:	TRIM8, Genomics, Monogenic, Epilepsy, FSGS, SRNS, Nuclear Body, Animals, Mice
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	108
Number:	2
Page Range:	357-367
Date:	4 February 2021
Official Publication:	https://doi.org/10.1016/j.ajhg.2021.01.008
PubMed:	View item in PubMed

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