WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome

Kim, Yeon-Joo; Osborn, Daniel P. S.; Lee, Ji-Young; Araki, Masatake; Araki, Kimi; Mohun, Timothy J.; Känsäkoski, Johanna; Brandstack, Nina; Kim, Hyun-Taek; Miralles, Francisco Felip; Kim, Cheol-Hee; Brown, Nigel A.; Kim, Hyung‐Goo; Martinez-Barbera, Juan Pedro; Ataliotis, Paris; Raivio, Taneli; Layman, Lawrence C.; Kim, Soohyun

doi:10.1101/200154

Cited by 5 publications

(6 citation statements)

References 69 publications

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“…Similarly, variations in the WDR11 gene have been associated with ciliopathy-related disorders and Kallmann syndrome. Associated features include pituitary dysgenesis and obesity [Kim et al, 2018].…”

Section: Discussionmentioning

confidence: 99%

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Alfadhel¹,

Umair²,

Almuzzaini³

et al. 2021

Mol Syndromol

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Ciliopathies constitute heterogeneous disorders that result from mutations in ciliary proteins. These proteins play an important role in the development of organs, physiology, and signaling pathways, and sequence variations in the genes encoding these proteins are associated with multisystem disorders. In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner in a nonconsanguineous Saudi family. The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4–1G>C; NM_024926.3) in the tetratricopeptide repeat domain 26 (TTC26) gene located in chromosome 7q34, which cosegregated perfectly with the disease phenotype. qRT-PCR revealed a substantial decrease in the expression of the TTC26 gene as compared to the normal control, suggesting the pathogenicity of the identified variant. This report further strengthens the evidence that homozygous variants in the TTC26 gene cause severe ciliopathies with diverse phenotypes. We named this newly characterized condition as BRENS syndrome, which stands for biliary, renal, neurological, and skeletal features.

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Section: Discussionmentioning

confidence: 99%

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Alfadhel¹,

Umair²,

Almuzzaini³

et al. 2021

Mol Syndromol

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“…Slides were incubated for 24 hours in primary antibodies in a humid chamber. The following antibodies and concentrations were used: mouse-YAP (1:100, Santa Cruz, #101199, (Szymaniak et al, 2017;Zanconato et al, 2015)), rabbit-pYAP (1:500, Cell Signaling, #4911, (Heallen et al, 2013)), rabbit-SOX9 (1:500, Millipore, AB5535, (Poché et al, 2008)), mouse-TEAD1 (1:1000, BD transduction, 610923, (Cao et al, 2008)), mouse-SOX2 (1:500, Santa Cruz, 365823, (Xiao et al, 2018a)), rabbit-GFAP (1:1000, Dako, Z0334, (Poché et al, 2016)), rabbit-PH3 (1:500, Millipore, 06-570) (Barrasso et al, 2018), rabbit-Ki67 (1:500, Abcam 15580, (Poché et al, 2016)), rabbit-Cyclin D1 (1:1000, Thermo Fisher, 9104, (Poché et al, 2016)), mouse-Cyclin D3 (1:200, Abcam, 28283, ), rabbit-GFP (1:500, Rockland, 600-401-215, (Kovalchuk et al, 2015)), mouse-Flag (1:250, Sigma, F1804, (Zanconato et al, 2015)), chick-beta-Gal (1:500, Abcam, 936, (Kim et al, 2018)), mouse-GS (1:500, Chemicon, MAB302, (Rueda et al, 2016)), mouse-HuC/D (1:100, Invitrogen, A-21271, (Jorstad et al, 2017;Ueki et al, 2015)).…”

Section: Methods Detailsmentioning

confidence: 99%

The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming

et al. 2019

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SUMMARY In response to retinal damage, the Müller glial cells (MGs) of the zebrafish retina have the ability to undergo a cellular reprogramming event in which they enter the cell cycle and divide asymmetrically, thereby producing multipotent retinal progenitors capable of regenerating lost retinal neurons. However, mammalian MGs do not exhibit such a proliferative and regenerative ability. Here, we identify Hippo pathway-mediated repression of the transcription cofactor YAP as a core regulatory mechanism that normally blocks mammalian MG proliferation and cellular reprogramming. MG-specific deletion of Hippo pathway components Lats1 and Lats2 , as well as transgenic expression of a Hippo non-responsive form of YAP (YAP5SA), resulted in dramatic Cyclin D1 upregulation, loss of adult MG identity, and attainment of a highly proliferative, progenitor-like cellular state. Our results reveal that mammalian MGs may have latent regenerative capacity that can be stimulated by repressing Hippo signaling.

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“…The primary cilium has emerged as an important organelle that controls signal transduction during development and tissue homeostasis. Both, short or abnormally elongated cilia have been reported in patients with ciliopathies and contribute to dysfunctional signalling, highlighting the importance of understanding cilia length regulation (Kim et al , 2018; Oh & Katsanis, 2013; Ramsbottom et al , 2018; Baala et al , 2007; Aguilar et al , 2012). Whereas the majority of studies were so far dedicated to the analysis of cilia assembly and disassembly, little is known about how cilia length is maintained at steady-state.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, relatively long cilia are reported in neurons (8-10µm), whilst much shorter cilia are present in chondrocytes (2µm) (Wann & Knight, 2012; Miyoshi et al , 2014). Variations in the physiological length of cilia causing shortening or over-elongation are reported in ciliopathies, indicated that keeping proper cilia length in each tissue is vital for their signalling function (Guen et al , 2016; Ramsbottom et al , 2018; Leightner et al , 2013; May-Simera et al , 2018; Reiter & Leroux, 2017; Kim et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

Balancing the length of distal tip is key for stability and signalling function of primary cilia

Kanamaru

Neuner

Kurtulmus

et al. 2021

Preprint

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Primary cilia are antenna-like organelles required for signalling transduction. How cilia structure is mechanistically maintained at steady-state to promote signalling is largely unknown. Here, we define that mammalian primary cilia are formed by middle and distal segments, in analogy to sensory cilia of lower eukaryotes. The analysis of middle/distal segmentation indicated that perturbations leading to cilia over-elongation influenced middle or distal segment length with a different impact on cilia behaviour. We identified Septins as novel repressors of distal segment growth. We show that Septins control the localisation of MKS3 and CEP290 required for a functional transition zone, and through this the entrance of the microtubule-capping kinesin KIF7, a cilia-growth inhibitor, into the cilium. Live-cell imaging and analysis of sonic-hedgehog (SHH) signalling activation established that distal segment over-extension increased cilia excision events and decreased SHH activation. Our data underlies the importance of understanding cilia segmentation for length control and cilia-dependent signalling.

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WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome

Cited by 5 publications

References 69 publications

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming

Balancing the length of distal tip is key for stability and signalling function of primary cilia

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