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 - 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 - PKD
KW - cilia
KW - ciliopathy
KW - cyst
KW - fibrosis
KW - kidney
KW - liver
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 -