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A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease

Patient variants in Tubby Like Protein-3 (TULP3) have recently been associated with progressive fibrocystic disease in tissues and organs. TULP3 is a ciliary trafficking protein that links membrane-associated proteins to the intraflagellar transport complex A. In mice, mutations in Tulp3 drive pheno...

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Autores principales: Jafari Khamirani, Hossein, Palicharla, Vivek Reddy, Dastgheib, Seyed Alireza, Dianatpour, Mehdi, Imanieh, Mohammad Hadi, Tabei, Seyed Sajjad, Besse, Whitney, Mukhopadhyay, Saikat, Liem, Karel F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585244/
https://www.ncbi.nlm.nih.gov/pubmed/36276950
http://dx.doi.org/10.3389/fgene.2022.1021037
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author Jafari Khamirani, Hossein
Palicharla, Vivek Reddy
Dastgheib, Seyed Alireza
Dianatpour, Mehdi
Imanieh, Mohammad Hadi
Tabei, Seyed Sajjad
Besse, Whitney
Mukhopadhyay, Saikat
Liem, Karel F.
author_facet Jafari Khamirani, Hossein
Palicharla, Vivek Reddy
Dastgheib, Seyed Alireza
Dianatpour, Mehdi
Imanieh, Mohammad Hadi
Tabei, Seyed Sajjad
Besse, Whitney
Mukhopadhyay, Saikat
Liem, Karel F.
author_sort Jafari Khamirani, Hossein
collection PubMed
description Patient variants in Tubby Like Protein-3 (TULP3) have recently been associated with progressive fibrocystic disease in tissues and organs. TULP3 is a ciliary trafficking protein that links membrane-associated proteins to the intraflagellar transport complex A. In mice, mutations in Tulp3 drive phenotypes consistent with ciliary dysfunction which include renal cystic disease, as part of a ciliopathic spectrum. Here we report two sisters from consanguineous parents with fibrocystic renal and hepatic disease harboring a homozygous missense mutation in TULP3 (NM_003324.5: c.1144C>T, p.Arg382Trp). The R382W patient mutation resides within the C-terminal Tubby domain, a conserved domain required for TULP3 to associate with phosphoinositides. We show that inner medullary collecting duct-3 cells expressing the TULP3 R382W patient variant have a severely reduced ability to localize the membrane-associated proteins ARL13b, INPP5E, and GPR161 to the cilium, consistent with a loss of TULP3 function. These studies establish Arginine 382 as a critical residue in the Tubby domain, which is essential for TULP3-mediated protein trafficking within the cilium, and expand the phenotypic spectrum known to result from recessive deleterious mutations in TULP3.
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spelling pubmed-95852442022-10-22 A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease Jafari Khamirani, Hossein Palicharla, Vivek Reddy Dastgheib, Seyed Alireza Dianatpour, Mehdi Imanieh, Mohammad Hadi Tabei, Seyed Sajjad Besse, Whitney Mukhopadhyay, Saikat Liem, Karel F. Front Genet Genetics Patient variants in Tubby Like Protein-3 (TULP3) have recently been associated with progressive fibrocystic disease in tissues and organs. TULP3 is a ciliary trafficking protein that links membrane-associated proteins to the intraflagellar transport complex A. In mice, mutations in Tulp3 drive phenotypes consistent with ciliary dysfunction which include renal cystic disease, as part of a ciliopathic spectrum. Here we report two sisters from consanguineous parents with fibrocystic renal and hepatic disease harboring a homozygous missense mutation in TULP3 (NM_003324.5: c.1144C>T, p.Arg382Trp). The R382W patient mutation resides within the C-terminal Tubby domain, a conserved domain required for TULP3 to associate with phosphoinositides. We show that inner medullary collecting duct-3 cells expressing the TULP3 R382W patient variant have a severely reduced ability to localize the membrane-associated proteins ARL13b, INPP5E, and GPR161 to the cilium, consistent with a loss of TULP3 function. These studies establish Arginine 382 as a critical residue in the Tubby domain, which is essential for TULP3-mediated protein trafficking within the cilium, and expand the phenotypic spectrum known to result from recessive deleterious mutations in TULP3. Frontiers Media S.A. 2022-10-07 /pmc/articles/PMC9585244/ /pubmed/36276950 http://dx.doi.org/10.3389/fgene.2022.1021037 Text en Copyright © 2022 Jafari Khamirani, Palicharla, Dastgheib, Dianatpour, Imanieh, Tabei, Besse, Mukhopadhyay and Liem. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Jafari Khamirani, Hossein
Palicharla, Vivek Reddy
Dastgheib, Seyed Alireza
Dianatpour, Mehdi
Imanieh, Mohammad Hadi
Tabei, Seyed Sajjad
Besse, Whitney
Mukhopadhyay, Saikat
Liem, Karel F.
A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
title A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
title_full A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
title_fullStr A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
title_full_unstemmed A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
title_short A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
title_sort pathogenic variant of tulp3 causes renal and hepatic fibrocystic disease
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585244/
https://www.ncbi.nlm.nih.gov/pubmed/36276950
http://dx.doi.org/10.3389/fgene.2022.1021037
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