Genes and molecular pathways underpinning ciliopathies

Reiter, Jeremy F.; Leroux, Michel R.

doi:10.1038/nrm.2017.60

Cited by 1,238 publications

(1,319 citation statements)

References 200 publications

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“…Up to now, nearly 200 genes have been reported to be associated with ciliopathies [2]. Only about 50% of the genes accounting for various types of ciliopathies shows a high degree of overlapping clinical features and results from a few causative genes, which poses an increasing challenge for physicians to make the right diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the dysfunction of certain proteins in cilia causes the altered functions of cilia and influences the transduction of these signaling pathways, resulting in different ciliopathies. Due to the ubiquitous existence and the indispensable role for various signaling transduction, primary cilia have been considered to have critical roles and are involved in the pathogenesis of the non-motile ciliopathies [2]. In this review, we focus on the main functions of tectonic proteins in primary cilia and tectonic proteins-related ciliopathies.…”

Section: Primary Ciliamentioning

confidence: 99%

“…As the primary cilia present on almost each mammalian cell, non-motile ciliopathies involve multiple systems and organs and thus exhibit appreciable clinical heterogeneities. Although more than 100 genes that are associated with ciliopathies have been identified [2], mutations in one certain gene can induce one or more phenotypes in multiple systems. Therefore, the complexity of the non-motile ciliopathies renders diagnoses and treatments extremely daunting.…”

Section: Introductionmentioning

confidence: 99%

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Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

Gong

Wang

et al. 2018

Cell Physiol Biochem

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Primary cilium is a ubiquitous, tiny organelle on the apex of the mammalian cells. Non-motile (primary) ciliopathies are diseases caused by the dysfunction of the primary cilium and they are characterized by diverse clinical and genetic heterogeneity. To date, nearly 200 genes have been shown to be associated with primary ciliopathies. Among them, tectonic genes are the important causative genes of ciliopathies. Tectonic proteins including TCTN1, TCTN2, and TCTN3 are important component proteins residing at the transition zone of cilia. Indeed, many ciliopathies have been reported to involve tectonics mutations, highlighting a pivotal role for tectonic proteins in ciliary functions. However, the specific functions of tectonic proteins remain largely enigmatic. Herein, we discuss the recent advances on the localization and structure of tectonic proteins and the functions of tectonic proteins. The increasing line of evidences demonstrates that tectonic proteins are required for ciliogenesis and regulate ciliary membrane composition. More importantly, Tectonic proteins play a vital role in the regulation of the Sonic Hedgehog (Shh) pathway; Tectonic deficient mice show the Shh pathway-related developmental defects. Tectonic proteins share similar functions including neural patterning and Gli3 processing but also each has a unique and indispensable role in the ciliogenesis and signaling pathways. At the same time, the mutations of tectonic genes are the causes of a serial of primary ciliopathies including Meckel-Gruber syndrome, Oral-facial-digital syndrome, and Joubert syndrome. Therefore, full understanding of functions of tectonic proteins will help to crack ciliopathies and improve life quality of patients by future gene therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Primary Ciliamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

Gong

Wang

et al. 2018

Cell Physiol Biochem

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“…The molecular mechanism(s) involved in polycystic kidney disease are still poorly understood. Changes in cell proliferation, planar cell polarity, and defects in primary cilium structure or signaling have been implicated in polycystic kidney disease [146–150]. Inflammation and fibrosis also play an important role in the pathogenesis of cystic renal disease [151].…”

Section: Molecular and Physiological Functions Of Glis1–3mentioning

confidence: 99%

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

Jetten

2018

Cell. Mol. Life Sci.

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Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-Similar 1–3 (GLIS1–3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1–3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

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“…Broad dysfunction of ciliary trafficking causes human genetic diseases and syndromic disorders collectively known as ciliopathies (Reiter and Leroux, 2017). The transition zone and basal body multiprotein complexes NPHP-JBTS-MKS and BBS participate in ciliary morphogenesis and gating.…”

Section: Introductionmentioning

confidence: 99%

The Arf GEF GBF1 and Arf4 synergize with the sensory receptor cargo, rhodopsin, to regulate ciliary membrane trafficking

Wang

Fresquez

Kandachar

et al. 2017

Journal of Cell Science

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The small GTPase Arf4 and the Arf GTPase-activating protein (GAP) ASAP1 cooperatively sequester sensory receptor cargo into transport carriers targeted to primary cilia, but the input that drives Arf4 activation in this process remains unknown. Here, we show, by using frog retinas and recombinant human proteins, that during the carrier biogenesis from the photoreceptor Golgi/trans-Golgi network (TGN) a functional complex is formed between Arf4, the Arf guanine nucleotide exchange factor (GEF) GBF1 and the light-sensing receptor, rhodopsin. Rhodopsin and Arf4 bind the regulatory Nterminal dimerization and cyclophillin-binding (DCB)-homology upstream of Sec7 (HUS) domain of GBF1. The complex is sensitive to Golgicide A (GCA), a selective inhibitor of GBF1 that accordingly blocks rhodopsin delivery to the cilia, without disrupting the photoreceptor Golgi. The emergence of newly synthesized rhodopsin in the endomembrane system is essential for GBF1-Arf4 complex formation in vivo. Notably, GBF1 interacts with the Arf GAP ASAP1 in a GCA-resistant manner. Our findings indicate that converging signals on GBF1 from the influx of cargo into the Golgi/ TGN and the feedback from Arf4, combined with input from ASAP1, control Arf4 activation during sensory membrane trafficking to primary cilia.

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Genes and molecular pathways underpinning ciliopathies

Cited by 1,238 publications

References 200 publications

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

The Arf GEF GBF1 and Arf4 synergize with the sensory receptor cargo, rhodopsin, to regulate ciliary membrane trafficking

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