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 ORCID: 0000-0003-2952-5030, Kitzler, Thomas M., Klambt, Verena ORCID: 0000-0003-1180-0794, Kolb, Amy, Mao, Youying, El Achkar, Christelle Moufawad, Mitrotti, Adele, Martino, Jeremiah, Beck, Bodo B., Altmuller, Janine ORCID: 0000-0003-4372-1521, Benz, Marcus R., Yano, Shoji, Mikati, Mohamad A., Gunduz, Talha, Cope, Heidi ORCID: 0000-0003-0586-9277, Shashi, Vandana, Trachtman, Howard ORCID: 0000-0001-7447-9489, Bodria, Monica, Caridi, Gianluca ORCID: 0000-0001-6700-3001, 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 ORCID: 0000-0002-7878-6096, Koziell, Ania B., Muorah, Mordi, Saleem, Moin A., Hoefele, Julia ORCID: 0000-0002-7917-7129, Riedhammer, Korbinian M., Gharavi, Ali G., Jobanputra, Vaidehi, Pierce-Hoffman, Emma, Seaby, Eleanor G., O'Donnell-Luria, Anne ORCID: 0000-0001-6418-9592, 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 and Sanna-Cherchi, Simone (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). S. 357 - 368. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 3 10(-11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 3 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Weng, Patricia L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Majmundar, Amar J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, KamalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Tze Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shril, ShirleeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jin, GinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Musgrove, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, MinxianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahram, Dina F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aggarwal, Vimla S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bier, Louise E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinzen, Erin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Onuchic-Whitford, Ana C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mann, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buerger, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, RonenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deutsch, KonstantinUNSPECIFIEDorcid.org/0000-0003-2952-5030UNSPECIFIED
Kitzler, Thomas M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klambt, VerenaUNSPECIFIEDorcid.org/0000-0003-1180-0794UNSPECIFIED
Kolb, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mao, YouyingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El Achkar, Christelle MoufawadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitrotti, AdeleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martino, JeremiahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDorcid.org/0000-0003-4372-1521UNSPECIFIED
Benz, Marcus R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yano, ShojiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mikati, Mohamad A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunduz, TalhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cope, HeidiUNSPECIFIEDorcid.org/0000-0003-0586-9277UNSPECIFIED
Shashi, VandanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trachtman, HowardUNSPECIFIEDorcid.org/0000-0001-7447-9489UNSPECIFIED
Bodria, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caridi, GianlucaUNSPECIFIEDorcid.org/0000-0001-6700-3001UNSPECIFIED
Pisani, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiaccadori, EnricoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
AbuMaziad, Asmaa S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez-Agosto, Julian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yadin, OraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuckerman, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, ArangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John-Kroegel, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tyndall, Amanda, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parboosingh, Jillian S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Innes, A. MicheilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bierzynska, AgnieszkaUNSPECIFIEDorcid.org/0000-0002-7878-6096UNSPECIFIED
Koziell, Ania B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muorah, MordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saleem, Moin A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefele, JuliaUNSPECIFIEDorcid.org/0000-0002-7917-7129UNSPECIFIED
Riedhammer, Korbinian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gharavi, Ali G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jobanputra, VaidehiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pierce-Hoffman, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seaby, Eleanor G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Donnell-Luria, AnneUNSPECIFIEDorcid.org/0000-0001-6418-9592UNSPECIFIED
Rehm, Heidi L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mane, ShrikantUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
D'Agati, Vivette D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pollak, Martin R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghiggeri, Gian MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lifton, Richard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldstein, David B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davis, Erica E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hildebrandt, FriedhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanna-Cherchi, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-606857
DOI: 10.1016/j.ajhg.2021.01.008
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 108
Number: 2
Page Range: S. 357 - 368
Date: 2021
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RESISTANT NEPHROTIC SYNDROME; NONSENSE-MEDIATED DECAY; MESSENGER-RNA; MUTATIONS; REVEALS; DISEASE; FATHERS; INTRON; MOUSE; AGEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60685

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