A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease

Hossein Jafari Khamirani, Vivek Reddy Palicharla, Seyed Alireza Dastgheib, Mehdi Dianatpour, Mohammad Hadi Imanieh, Seyed Sajjad Tabei, Whitney Besse, Saikat Mukhopadhyay, Karel F. Liem

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number1021037
JournalFrontiers in Genetics
StatePublished - Oct 7 2022


  • cilia
  • ciliopathy
  • cyst
  • fibrosis
  • kidney
  • liver
  • PKD
  • tubby domain

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)


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