TMEM17

Cilia effects upon perturbation of TMEM17

Cilia number / % ciliated:

No effect

Loss-of-function effect:

Shorter cilia

Ciliogenesis screen results (4 screens)

• Kim2016: Not Reported
• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-2.78) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: Positive Regulator (Hh signaling, casTLE effect=-2.91) PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381

Phenotypes

Mouse phenotype:

increased grip strength, unresponsive to tactile stimuli, preweaning lethality, complete penetrance, abnormal blood vessel morphology, no spontaneous movement, abnormal eye morphology, hemorrhage

Ciliopathy associations

• Joubert Syndrome
• Meckel-Gruber Syndrome
• Orofaciodigital Syndrome

Subcellular localization

basal body, transition zone

Functional category

• Ciliary assembly/disassembly
• Ciliary membrane
• Transition zone

Function

CEP-290-dependent transition zone protein that facilitates cilium formation, being necessary for ciliogenesis, mutated in OFD6 (26982032). Specifically, PC from OFD6 patient cells are longer with altered protein composition and impaired ability to transduce the Sonic Hedgehog (SHH) pathway. We further modeled the Arg94Trp variant in a C. elegans model system, as well as the two previously reported variants (Gly101Val and Asn102Lys) with unknown pathological mechanisms [39, 41], and found that all three disrupt TMEM-17 function. Together, our findings establish TMEM17 as a bona fide ciliopathy gene with a broad phenotypic spectrum and provide evidence that deleterious missense variants in TMEM17 involve amino acids that reside within a transmembrane “mutational hotspot” crucial for its biological function. (40841990)