TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone

Roberson, Elle C.; Dowdle, William E.; Ozantürk, Ayşegül; Garcia-Gonzalo, Francesc R.; Li, Chunmei; Halbritter, Jan; Elkhartoufi, Nadia; Porath, Jonathan D.; Cope, Heidi; Ashley-Koch, Allison E.; Gregory, Simon G.; Thomas, Sophie; Sayer, John A.; Saunier, Sophie; Otto, Edgar A.; Katsanis, Nicholas; Davis, Erica E.; Attié‐Bitach, Tania; Hildebrandt, Friedhelm; Leroux, Michel R.; Reiter, Jeremy F.

doi:10.1083/jcb.201411087

Cited by 97 publications

(136 citation statements)

References 52 publications

(144 reference statements)

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“…We found that Tctn1, a transition zone protein essential for vertebrate Hh signaling (Garcia-Gonzalo et al 2011; Roberson et al 2015), is required for the ciliary localization of Inpp5e (Fig.2A-B). Because Inpp5e can convert PI(4,5)P 2 into PI(4)P, we hypothesized that Inpp5e affects the relative levels of these lipids in the ciliary membrane.…”

Section: Resultsmentioning

confidence: 88%

Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling

et al. 2015

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SUMMARY Primary cilia interpret vertebrate Hedgehog (Hh) signals. Why cilia are essential for signaling is unclear. One possibility is that some forms of signaling require a distinct membrane lipid composition, found at cilia. We found that the ciliary membrane contains a particular phosphoinositide, PI(4)P, whereas a different phosphoinositide, PI(4,5)P2, is restricted to the membrane of the ciliary base. This distribution is created by Inpp5e, a ciliary phosphoinositide 5-phosphatase. Without Inpp5e, ciliary PI(4,5)P2 levels are elevated and Hh signaling is disrupted. Inpp5e limits the ciliary levels of inhibitors of Hh signaling, including Gpr161 and the PI(4,5)P2-binding protein Tulp3. Increasing ciliary PI(4,5)P2 levels or conferring the ability to bind PI(4)P on Tulp3 increases the ciliary localization of Tulp3. Lowering Tulp3 in cells lacking Inpp5e reduces ciliary Gpr161 levels and restores Hh signaling. Therefore, Inpp5e regulates ciliary membrane phosphoinositide composition, and Tulp3 reads out ciliary phosphoinositides to control ciliary protein localization, enabling Hh signaling.

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Section: Resultsmentioning

confidence: 88%

Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling

et al. 2015

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“…Previous studies showed that three Tctn proteins interact with one another and some of the known proteins localizing at the transition zone (Chih et al, 2011; Garcia-Gonzalo et al, 2011; Roberson et al, 2015; Sang et al, 2011). To confirm those studies, we performed coimmunoprecipitation using HEK293 cells overexpressing various transition-zone-localized proteins.…”

Section: Resultsmentioning

confidence: 99%

“…How ciliary proteins are selectively transported into cilia remains poorly understood. Nevertheless, the integrity of the protein complexes localizing to this compartment appears to be essential, as several recent studies show that loss of each single protein component within a protein complex all results in defects in membrane protein composition in cilia (Chih et al, 2011; Garcia-Gonzalo et al, 2011; Roberson et al, 2015; Sang et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse

Wang

Meng

et al. 2017

Developmental Biology

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Tctn1, Tctn2, and Tctn3 are membrane proteins that localize at the transition zone of primary cilia. Tctn1 and Tctn2 mutations have been reported in both humans and mice, but Tctn3 mutations have been reported only in humans. It is also not clear whether the three Tctn proteins are functionally conserved with respect to ciliogenesis and Hedgehog (Hh) signaling. In the present study, we report that loss of Tctn3 gene function in mice results in a decrease in ciliogenesis and Hh signaling. Consistent with this, Tctn3 mutant mice exhibit holoprosencephaly and randomized heart looping and lack the floor plate in the neural tube, the phenotypes similar to those of Tctn1 and Tctn2 mutants. We also show that overexpression of Tctn3, but not Tctn1 or Tctn2, can rescue ciliogenesis in Tctn3 mutant cells. Similarly, replacement of Tctn3 with Tctn1 or Tctn2 in the Tctn3 gene locus results in reduced ciliogenesis and Hh signaling, holoprosencephaly, and randomized heart looping. Surprisingly, however, the neural tube patterning and the proteolytic processing of Gli3 (a transcription regulator for Hh signaling) into a repressor, both of which are usually impaired in ciliary gene mutants, are normal. These results suggest that Tctn1, Tctn2, and Tctn3 are functionally divergent with respect to their role in ciliogenesis and Hh signaling but conserved in neural tube patterning and Gli3 processing.

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“…27 Unsurprisingly, there are numerous examples of variant TMEM proteins in human genetic disorders, [28][29][30][31][32][33][34] and in that context, we do gain pathomechanistic clues about the disorder. We have reported enrichment of TMEM domains in the ciliary proteome, 35 raising the possibility that the present constellation of phenotypes could be part of the ciliopathy spectrum.…”

Section: Renal Defectsmentioning

confidence: 99%

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Ta‐Shma

Khan

Vivante

et al. 2017

The American Journal of Human Genetics

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Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.Whole-exome and whole-genome sequencing (WES and WGS, respectively) have accelerated the expansion of the repertoire of human loci underscoring Mendelian phenotypes to account for~3,000 human genes (15%).1 Nonetheless, the diagnostic yield remains <50%, 2-4 suggesting that the majority of disease-causing lesions are yet to be identified and that a significant fraction of this genetic burden is likely to be contributed by ultra-rare or private mutations. To contribute to the saturation of the morbid human genome as a means of improving both diagnostic value and mechanistic insight, we undertook the systematic sequencing of families affected by suspected genetic disorders, with an emphasis on congenital syndromic traits. Here, we report the genetic and functional dissection of affected individuals with a genetically undiagnosed syndrome characterized by cardiac, CNS, renal, and digit abnormalities in two unrelated consanguineous pedigrees. We show that the likely molecular cause, homozygous truncating mutations in TMEM260, affect the functions of one of the two established isoforms transcribed from this locus, thereby demonstrating the necessity of the long isoform for the development of multiple tissues. We consulted family 1, a con...

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TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone

Abstract: TMEM231, a functional component of the MKS complex at the ciliary transition zone, is mutated in orofaciodigital syndrome type 3 and Meckel syndrome.

Cited by 97 publications

References 52 publications

Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling

Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling

Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

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