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, Jahrgang 108, Nr. 2, 04.02.2021, S. 357-367.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -