Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations

Devane, John; Ott, Elisabeth; Olinger, Eric; Epting, Daniel; Decker, Eva L.; Friedrich, Anja; Bachmann, Nadine; Renschler, Gina; Eisenberger, Tobias; Briem-Richter, Andrea; Grabhorn, Enke; Powell, Laura; Wilson, I. J.; Rice, S.J.; Miles, Colin; Wood, Katrina; Trivedi, Palak; Hirschfield, Gideon M.; Pietrobattista, Andrea; Wohler, Elizabeth; Mezina, Anya; Sobreira, Nara; Agolini, Emanuele; Maggiore, Giuseppe; Dahmer-Heath, Mareike; Yılmaz, Ali; Boerries, Melanie; Metzger, Patrick Bastos; Schell, Christoph; Grünewald, Inga; Konrad, Martin; König, Jens; Schlevogt, Bernhard; Sayer, John A.; Bergmann, Carsten

doi:10.1016/j.ajhg.2022.03.015

Cited by 31 publications

(25 citation statements)

References 47 publications

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“…In humans, a mutation within the tubby domain is associated with early onset obesity and retinal degeneration ( 23 ). Recently, mutations in human TULP3, a tubby homolog that shares the conserved tubby domain, were found to cause multisystemic ciliopathy associated with liver fibrosis, fibrocystic kidney disease, and cardiomyopathy ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Two cooperative binding sites sensitize PI(4,5)P ₂ recognition by the tubby domain

et al. 2022

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Phosphoinositides (PIs) are lipid signaling molecules that operate by recruiting proteins to cellular membranes via PI recognition domains. The dominant PI of the plasma membrane is phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ]. One of only two PI(4,5)P 2 recognition domains characterized in detail is the tubby domain. It is essential for targeting proteins into cilia involving reversible membrane association. However, the PI(4,5)P 2 binding properties of tubby domains have remained enigmatic. Here, we used coarse-grained molecular dynamics simulations to explore PI(4,5)P 2 binding by the prototypic tubby domain. The comparatively low PI(4,5)P 2 affinity of the previously described canonical binding site is underpinned in a cooperative manner by a previously unknown, adjacent second binding site. Mutations in the previously unknown site impaired PI(4,5)P 2 -dependent plasma membrane localization in living cells and PI(4,5)P 2 interaction in silico, emphasizing its importance for PI(4,5)P 2 affinity. The two-ligand binding mode may serve to sharpen the membrane association-dissociation cycle of tubby-like proteins that underlies delivery of ciliary cargo.

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Section: Introductionmentioning

confidence: 99%

Two cooperative binding sites sensitize PI(4,5)P ₂ recognition by the tubby domain

et al. 2022

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“…Variants in TULP3 have recently been identified in patients with variable and progressive organ fibrosis (Devane et al, 2022). The TULP3 locus contains 11 exons and encodes a 442 amino acid protein with a N-terminal IFT-A binding domain and a C-terminal Tubby domain (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…Many genes are involved with building a functional cilium and the severity and nature of the disease resulting from their mutations depend on the individual gene affected and the nature of the mutation. Recently, variants in the Tubby like protein-3 (TULP3) have been associated with multisystem fibrotic disease in patients (Devane et al, 2022). TULP3 (Tubby like protein-3; MIM: 604730) encodes a member of the Tubby domain family of proteins (Mukhopadhyay and Jackson, 2011) which contain a signature carboxy-terminal Tubby domain that functions to bind selectively to membrane phosphoinositides (Santagata et al, 2001;Mukhopadhyay et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease

Khamirani

Palicharla²,

Dastgheib³

et al. 2022

Front. Genet.

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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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“…To facilitate the WES analysis, we developed a list of 502 genes associated with a Mendelian disease with potential liver phenotypes ( Figure 3 ). Several new genetic disorders, such as TULP3 [41], KIF12, USP54 [42], KCNN3 [43,44], GIMAP5 [9] and so on, were discovered and recently reported to cause liver phenotypes. These discoveries coupled with their detailed annotated phenotypes provide an important resource to look for a genetic diagnosis for those patients with a related clinical phenotype and available WES result.…”

Section: Discussionmentioning

confidence: 99%

Challenges associated with diagnostic exome sequencing in liver diseases

Kong

Bogyo

Kapoor

et al. 2022

Preprint

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BackgroundWe investigated the diagnostic yield of exome sequencing in patients with liver diseases.MethodsWe retrospectively analyzed WES data for 10,801 individuals: 758 patients with CLD, 7,856 self-declared healthy controls (HC), and 2,187 patients with chronic kidney disease (CKD). We searched for variants in a total of 502 genes causing Mendelian disorders with a primary or secondary liver disease phenotype. Candidate variants were previously reported as pathogenic (P) or likely pathogenic (LP) in the Human Gene Mutation Database (HGMD) or ClinVar databases, or novel protein-truncating variants (PTV).ResultsCandidate pathogenic variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After stringent filtering based on population minor allele frequency and variant annotation, P/LP variants were detected in 0.93% of the cohort, with a significant enrichment in the CLD cohort compared to the HC cohort (X2 test OR: 5.00, 95% CI:3.06-8.18). After two levels of manual annotation, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes. Clinically confirmed sequencing results had many implications for management: familial testing for early diagnosis and management, preventative screening for associated comorbidities, such as aneurysm or cancer. Some patients with previously undiagnosed congenital disorders of glycosylation, would benefit from selective nutritional management.ConclusionsGene list-based WES analysis provided a 5.7% diagnostic rate among patients with CLD, with implications regarding their clinical care and that of their families.

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Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations

Cited by 31 publications

References 47 publications

Two cooperative binding sites sensitize PI(4,5)P ₂ recognition by the tubby domain

Two cooperative binding sites sensitize PI(4,5)P ₂ recognition by the tubby domain

A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease

Challenges associated with diagnostic exome sequencing in liver diseases

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Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations

Cited by 31 publications

References 47 publications

Two cooperative binding sites sensitize PI(4,5)P 2 recognition by the tubby domain

Two cooperative binding sites sensitize PI(4,5)P 2 recognition by the tubby domain

A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease

Challenges associated with diagnostic exome sequencing in liver diseases

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Two cooperative binding sites sensitize PI(4,5)P ₂ recognition by the tubby domain

Two cooperative binding sites sensitize PI(4,5)P ₂ recognition by the tubby domain