TMEM107 Is a Critical Regulator of Ciliary Protein Composition and Is Mutated in Orofaciodigital Syndrome

Shylo, Natalia A.; Christopher, Kasey J.; Iglesias, Alejandro; Daluiski, Aaron; Weatherbee, Scott D.

doi:10.1002/humu.22925

Cited by 18 publications

(23 citation statements)

References 38 publications

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“…One of these, the NPHP complex, is mostly involved in the ciliopathy nephronophthisis (NPHP) and includes Nphp1, Nphp4, and Rpgrip1l (Mollet et al 2005; Arts et al 2007; Sang et al 2011). A second complex, involved mostly in Meckel (MKS) and Joubert (JBTS) syndromes and referred to as the MKS complex, includes the three Tectonic proteins (Tctn1, 2, 3), the three B9 domain proteins (Mks1, B9d1, B9d2), the coiled-coil proteins Cc2d2a and Cep290, Ahi1 and the transmembrane proteins Tmem67, Tmem216, Tmem17, Tmem231, Tmem107, and possibly others such as Tmem237 and Tmem218 (Chih et al 2011; Garcia-Gonzalo et al 2011; Huang et al 2011; Sang et al 2011; Christopher et al 2012; Barker et al 2014; Roberson et al 2015; Lambacher et al 2016; Li et al 2016; Shylo et al 2016). …”

Section: Transition Zonementioning

confidence: 99%

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

Garcia-Gonzalo

Reiter

2016

Cold Spring Harb Perspect Biol

229

227

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Cilia are plasma membrane protrusions that act as cellular propellers or antennae. To perform these functions, cilia must maintain a composition distinct from those of the contiguous cytosol and plasma membrane. The specialized composition of the cilium depends on the ciliary gate, the region at the ciliary base separating the cilium from the rest of the cell. The ciliary gate’s main structural features are electron dense struts connecting microtubules to the adjacent membrane. These structures include the transition fibers, which connect the distal basal body to the base of the ciliary membrane, and the Y-links, which connect the proximal axoneme and ciliary membrane within the transition zone. Both transition fibers and Y-links form early during ciliogenesis and play key roles in ciliary assembly and trafficking. Accordingly, many human ciliopathies are caused by mutations that perturb ciliary gate function.

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Section: Transition Zonementioning

confidence: 99%

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

Garcia-Gonzalo

Reiter

2016

Cold Spring Harb Perspect Biol

229

227

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“…Previously described mouse Tmem107 schlei and human patients with mutations in Tmem107, which encodes a ciliary transition zone protein, display fewer and abnormally shaped cilia, but no L-R patterning defects (Lambacher, et al, 2016;Shaheen, et al, 2015;Shylo, et al, 2016;Weatherbee, et al, 2009). In this study we report that Tmem107 null mice have left isomerism, resembling cilia mutants with global loss of cilia.…”

Section: Introductionmentioning

confidence: 48%

“…3A-D), which is consistent with cilia number reductions reported in Tmem107 schlei mouse mutants, and in human patients with mutations in TMEM107. (Christopher, Wang, Kong, et al, 2012;Lambacher, Bruel, van Dam, et al, 2016;Shaheen, et al, 2013;Shylo, Christopher, Iglesias, et al, 2016). The loss of ARL13B+ cilia in the endoderm, surrounding the node (Fig.…”

Section: Cilia In the Nodes Of Tmem107 Null Embryos Maintain Their Idmentioning

confidence: 99%

“…Tmem107 encodes a ciliary transition zone protein, required for the formation of a functional transition zone in primary cilia (Lambacher, Bruel, van Dam, et al, 2016;Shylo, Christopher, Iglesias, et al, 2016). Given the ubiquitous nature of primary cilia, we were surprised to see an enrichment of Tmem107 mRNA in the embryonic node at E7.5-8.5, compared to all other embryonic tissues ( Fig.…”

Section: Tmem107 Null Mutants Display Multiple Left-right Defectsmentioning

confidence: 99%

“…Midline cilia are necessary to establish midline barrier function TMEM107 and MKS1 are both required for normal cilia number and ciliary protein localization (Christopher, Wang, Kong, et al, 2012;Cui, Chatterjee, Francis, et al, 2011;Lambacher, Bruel, van Dam, et al, 2016;Shaheen, Faqeih, Alshammari, et al, 2013;Shylo, Christopher, Iglesias, et al, 2016;Weatherbee, Niswander and Anderson, 2009). The abnormal midline gene expression patterns in Mks1 krc and Tmem107 null mutants suggest MKS1 and TMEM107 may be required for cilia formation or function in the midline.…”

Section: Lefty1 Is Expressed In Mks1 Krc Transition Zone Mutants Withmentioning

confidence: 99%

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Presence of midline cilia supersedes the expression of Lefty1 in forming the midline barrier during the establishment of left-right asymmetry

Shylo

2018

Preprint

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Cilia in the vertebrate left-right organizer are required for the original break in left-right (L-R) symmetry. Subsequently, proper L-R patterning relies on asymmetric expression of Nodal in the lateral plate mesoderm (LPM). Lefty1, expressed in the embryonic midline, has been defined as the midline barrier, restricting the expression of Nodal to the left LPM. Here we use the mouse ciliary transition zone mutant Mks1 krc that has left isomerism and bilateral expression of the NODAL target Pitx2, to reveal that the expression of Lefty1 in the midline is insufficient for the establishment of the midline barrier. We further show through a comparison of two Tmem107 mutants that cilia in the midline are required to supplement Lefty1 expression and establish the functional midline barrier. Tmem107 null mutants have no cilia in the midline and display left isomerism due to the loss of the midline barrier, whereas Tmem107 schlei hypomorphic mutants have numerous cilia in the node and the midline, leading to normal Lefty1 expression and L-R patterning. This study reveals a novel role for cilia in the maintenance of L-R asymmetry.

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Genotype–phenotype correlates in Joubert syndrome: A review

Gana

Serpieri

Valente

2022

American J of Med Genetics Pt C

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Joubert syndrome (JS) is a genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the “molar tooth sign,” and variable organ involvement. Over 40 causative genes have been identified to date, explaining up to 94% of cases. To date, gene‐phenotype correlates have been delineated only for a handful of genes, directly translating into improved counseling and clinical care. For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. These examples highlight how an accurate description of the range of clinical symptoms associated with defects in each causative gene, including the rare ones, would better address prognosis and help guiding a personalized management. This review proposes to address this issue by assessing the available literature, to confirm known, as well as to propose rare gene‐phenotype correlates in JS.

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TMEM107 Is a Critical Regulator of Ciliary Protein Composition and Is Mutated in Orofaciodigital Syndrome

Cited by 18 publications

References 38 publications

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

Presence of midline cilia supersedes the expression of Lefty1 in forming the midline barrier during the establishment of left-right asymmetry

Genotype–phenotype correlates in Joubert syndrome: A review

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