TY - JOUR
T1 - A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
AU - Jafari Khamirani, Hossein
AU - Palicharla, Vivek Reddy
AU - Dastgheib, Seyed Alireza
AU - Dianatpour, Mehdi
AU - Imanieh, Mohammad Hadi
AU - Tabei, Seyed Sajjad
AU - Besse, Whitney
AU - Mukhopadhyay, Saikat
AU - Liem, Karel F.
N1 - Funding Information:
This project was funded by the National Institutes of Health (R01DK128089 to SM and R01NS097928 and R56DK132266 to KL), a PKD Foundation postdoctoral fellowship to VP (214F19a), and a PKD Foundation grant to KL (232G18). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
Copyright © 2022 Jafari Khamirani, Palicharla, Dastgheib, Dianatpour, Imanieh, Tabei, Besse, Mukhopadhyay and Liem.
PY - 2022/10/7
Y1 - 2022/10/7
N2 - 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.
AB - 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.
KW - cilia
KW - ciliopathy
KW - cyst
KW - fibrosis
KW - kidney
KW - liver
KW - PKD
KW - tubby domain
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U2 - 10.3389/fgene.2022.1021037
DO - 10.3389/fgene.2022.1021037
M3 - Article
C2 - 36276950
AN - SCOPUS:85140296225
SN - 1664-8021
VL - 13
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 1021037
ER -