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

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De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. / Weng, Patricia L; Majmundar, Amar J; Khan, Kamal; Lim, Tze Y; Shril, Shirlee; Jin, Gina; Musgrove, John; Wang, Minxian; Ahram, Dina F; Aggarwal, Vimla S; Bier, Louise E; Heinzen, Erin L; Onuchic-Whitford, Ana C; Mann, Nina; Buerger, Florian; Schneider, Ronen; Deutsch, Konstantin; Kitzler, Thomas M; Klämbt, Verena; Kolb, Amy; Mao, Youying; Moufawad El Achkar, Christelle; Mitrotti, Adele; Martino, Jeremiah; Beck, Bodo B; Altmüller, Janine; Benz, Marcus R; Yano, Shoji; Mikati, Mohamad A; Gunduz, Talha; Cope, Heidi; Shashi, Vandana; Trachtman, Howard; Bodria, Monica; Caridi, Gianluca; Pisani, Isabella; Fiaccadori, Enrico; AbuMaziad, Asmaa S; Martinez-Agosto, Julian A; Yadin, Ora; Zuckerman, Jonathan; Kim, Arang; John-Kroegel, Ulrike; Tyndall, Amanda V; Parboosingh, Jillian S; Innes, A Micheil; Bierzynska, Agnieszka; Koziell, Ania B; Muorah, Mordi; Saleem, Moin A; Hoefele, Julia; Riedhammer, Korbinian M; Gharavi, Ali G; Jobanputra, Vaidehi; Pierce-Hoffman, Emma; Seaby, Eleanor G; O'Donnell-Luria, Anne; Rehm, Heidi L; Mane, Shrikant; D'Agati, Vivette D; Pollak, Martin R; Ghiggeri, Gian Marco; Lifton, Richard P; Goldstein, David B; Davis, Erica E; Hildebrandt, Friedhelm; Sanna-Cherchi, Simone; Undiagnosed Diseases Network.

In: AM J HUM GENET, Vol. 108, No. 2, 04.02.2021, p. 357-367.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Weng, PL, Majmundar, AJ, Khan, K, Lim, TY, Shril, S, Jin, G, Musgrove, J, Wang, M, Ahram, DF, Aggarwal, VS, Bier, LE, Heinzen, EL, Onuchic-Whitford, AC, Mann, N, Buerger, F, Schneider, R, Deutsch, K, Kitzler, TM, Klämbt, V, Kolb, A, Mao, Y, Moufawad El Achkar, C, Mitrotti, A, Martino, J, Beck, BB, Altmüller, J, Benz, MR, Yano, S, Mikati, MA, Gunduz, T, Cope, H, Shashi, V, Trachtman, H, Bodria, M, Caridi, G, Pisani, I, Fiaccadori, E, AbuMaziad, AS, Martinez-Agosto, JA, Yadin, O, Zuckerman, J, Kim, A, John-Kroegel, U, Tyndall, AV, Parboosingh, JS, Innes, AM, Bierzynska, A, Koziell, AB, Muorah, M, Saleem, MA, Hoefele, J, Riedhammer, KM, Gharavi, AG, Jobanputra, V, Pierce-Hoffman, E, Seaby, EG, O'Donnell-Luria, A, Rehm, HL, Mane, S, D'Agati, VD, Pollak, MR, Ghiggeri, GM, Lifton, RP, Goldstein, DB, Davis, EE, Hildebrandt, F, Sanna-Cherchi, S & Undiagnosed Diseases Network 2021, 'De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis', AM J HUM GENET, vol. 108, no. 2, pp. 357-367. https://doi.org/10.1016/j.ajhg.2021.01.008

APA

Weng, P. L., Majmundar, A. J., Khan, K., Lim, T. Y., Shril, S., Jin, G., Musgrove, J., Wang, M., Ahram, D. F., Aggarwal, V. S., Bier, L. E., Heinzen, E. L., Onuchic-Whitford, A. C., Mann, N., Buerger, F., Schneider, R., Deutsch, K., Kitzler, T. M., Klämbt, V., ... Undiagnosed Diseases Network (2021). De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. AM J HUM GENET, 108(2), 357-367. https://doi.org/10.1016/j.ajhg.2021.01.008

Vancouver

Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G et al. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. AM J HUM GENET. 2021 Feb 4;108(2):357-367. https://doi.org/10.1016/j.ajhg.2021.01.008

Bibtex

@article{96f3e3cc25bf4c629e4a742b0bde6d2a,
title = "De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis",
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 = "Adult, Animals, Carrier Proteins/chemistry, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities/genetics, Epilepsy/genetics, Female, Glomerulosclerosis, Focal Segmental/genetics, Humans, Intranuclear Space/metabolism, Kidney/metabolism, Male, Mice, Mutation, Nephrotic Syndrome/genetics, Nerve Tissue Proteins/chemistry, Phenotype, Podocytes/metabolism, Exome Sequencing",
author = "Weng, {Patricia L} and Majmundar, {Amar J} and Kamal Khan and Lim, {Tze Y} and Shirlee Shril and Gina Jin and John Musgrove and Minxian Wang and Ahram, {Dina F} and Aggarwal, {Vimla S} and Bier, {Louise E} and Heinzen, {Erin L} and Onuchic-Whitford, {Ana C} and Nina Mann and Florian Buerger and Ronen Schneider and Konstantin Deutsch and Kitzler, {Thomas M} and Verena Kl{\"a}mbt and Amy Kolb and Youying Mao and {Moufawad El Achkar}, Christelle and Adele Mitrotti and Jeremiah Martino and Beck, {Bodo B} and Janine Altm{\"u}ller and Benz, {Marcus R} and Shoji Yano and Mikati, {Mohamad A} and Talha Gunduz and Heidi Cope and Vandana Shashi and Howard Trachtman and Monica Bodria and Gianluca Caridi and Isabella Pisani and Enrico Fiaccadori and AbuMaziad, {Asmaa S} and Martinez-Agosto, {Julian A} and Ora Yadin and Jonathan Zuckerman and Arang Kim and Ulrike John-Kroegel and Tyndall, {Amanda V} and Parboosingh, {Jillian S} and Innes, {A Micheil} and Agnieszka Bierzynska and Koziell, {Ania B} and Mordi Muorah and Saleem, {Moin A} and Julia Hoefele and Riedhammer, {Korbinian M} and Gharavi, {Ali G} and Vaidehi Jobanputra and Emma Pierce-Hoffman and Seaby, {Eleanor G} and Anne O'Donnell-Luria and Rehm, {Heidi L} and Shrikant Mane and D'Agati, {Vivette D} and Pollak, {Martin R} and Ghiggeri, {Gian Marco} and Lifton, {Richard P} and Goldstein, {David B} and Davis, {Erica E} and Friedhelm Hildebrandt and Simone Sanna-Cherchi and {Undiagnosed Diseases Network}",
note = "Copyright {\textcopyright} 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2021",
month = feb,
day = "4",
doi = "10.1016/j.ajhg.2021.01.008",
language = "English",
volume = "108",
pages = "357--367",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

AU - Weng, Patricia L

AU - Majmundar, Amar J

AU - Khan, Kamal

AU - Lim, Tze Y

AU - Shril, Shirlee

AU - Jin, Gina

AU - Musgrove, John

AU - Wang, Minxian

AU - Ahram, Dina F

AU - Aggarwal, Vimla S

AU - Bier, Louise E

AU - Heinzen, Erin L

AU - Onuchic-Whitford, Ana C

AU - Mann, Nina

AU - Buerger, Florian

AU - Schneider, Ronen

AU - Deutsch, Konstantin

AU - Kitzler, Thomas M

AU - Klämbt, Verena

AU - Kolb, Amy

AU - Mao, Youying

AU - Moufawad El Achkar, Christelle

AU - Mitrotti, Adele

AU - Martino, Jeremiah

AU - Beck, Bodo B

AU - Altmüller, Janine

AU - Benz, Marcus R

AU - Yano, Shoji

AU - Mikati, Mohamad A

AU - Gunduz, Talha

AU - Cope, Heidi

AU - Shashi, Vandana

AU - Trachtman, Howard

AU - Bodria, Monica

AU - Caridi, Gianluca

AU - Pisani, Isabella

AU - Fiaccadori, Enrico

AU - AbuMaziad, Asmaa S

AU - Martinez-Agosto, Julian A

AU - Yadin, Ora

AU - Zuckerman, Jonathan

AU - Kim, Arang

AU - John-Kroegel, Ulrike

AU - Tyndall, Amanda V

AU - Parboosingh, Jillian S

AU - Innes, A Micheil

AU - Bierzynska, Agnieszka

AU - Koziell, Ania B

AU - Muorah, Mordi

AU - Saleem, Moin A

AU - Hoefele, Julia

AU - Riedhammer, Korbinian M

AU - Gharavi, Ali G

AU - Jobanputra, Vaidehi

AU - Pierce-Hoffman, Emma

AU - Seaby, Eleanor G

AU - O'Donnell-Luria, Anne

AU - Rehm, Heidi L

AU - Mane, Shrikant

AU - D'Agati, Vivette D

AU - Pollak, Martin R

AU - Ghiggeri, Gian Marco

AU - Lifton, Richard P

AU - Goldstein, David B

AU - Davis, Erica E

AU - Hildebrandt, Friedhelm

AU - Sanna-Cherchi, Simone

AU - Undiagnosed Diseases Network

N1 - Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2021/2/4

Y1 - 2021/2/4

N2 - 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.

AB - 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.

KW - Adult

KW - Animals

KW - Carrier Proteins/chemistry

KW - Cell Line

KW - Child

KW - Child, Preschool

KW - Codon, Nonsense

KW - Developmental Disabilities/genetics

KW - Epilepsy/genetics

KW - Female

KW - Glomerulosclerosis, Focal Segmental/genetics

KW - Humans

KW - Intranuclear Space/metabolism

KW - Kidney/metabolism

KW - Male

KW - Mice

KW - Mutation

KW - Nephrotic Syndrome/genetics

KW - Nerve Tissue Proteins/chemistry

KW - Phenotype

KW - Podocytes/metabolism

KW - Exome Sequencing

U2 - 10.1016/j.ajhg.2021.01.008

DO - 10.1016/j.ajhg.2021.01.008

M3 - SCORING: Journal article

C2 - 33508234

VL - 108

SP - 357

EP - 367

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 2

ER -