Ift144

Primary cilia are essential cellular antennae that transmit external signals into intracellular responses. These sensory organelles perform crucial tasks in triggering intracellular signaling pathways, including those initiated by G protein-coupled receptors (GPCRs). Given the involvement of GPCRs in serum-induced signaling, we investigated the contribution of ciliary proteins in mitogen perception and cell proliferation. We found that depletion of cilia via IFT88 silencing impaired cell growth and repressed YAP activation against serum and its mitogenic constituents, namely lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P)...

Variants in WDR19 (IFT144) have been implicated as another possible cause of Stargardt disease. The purpose of this study was to compare longitudinal multimodal imaging of a WDR19-Stargardt patient, harboring p.(Ser485Ile) and a novel c.(3183+1_3184-1)_(3261+1_3262-1)del variant, with 43 ABCA4-Stargardt patients. Age at onset, visual acuity, Ishihara color vision, color fundus, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (OCT) images, microperimetry and electroretinography (ERG) were evaluated...

Ciliopathies are a group of genetic disorders caused by ciliary dysfunction. Thirty-five distinct multi-organ phenotypes have been recognized, with 187 genes associated. We performed a literature review of pancreatic involvement in ciliopathies and found that pancreatic disease is an uncommon phenotype described in only a handful of these genetic disorders. We present a case report of a pediatric patient with WDR19-related ciliopathy whose degree of pancreatic disease exceeds what has previously been reported in the literature for WDR19-related ciliopathies...

Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]...

Cilia sense and transduce extracellular signals via specific receptors. The intraflagellar transport (IFT) machinery mediates not only bidirectional protein trafficking within cilia but also the import/export of ciliary proteins across the ciliary gate. The IFT machinery is known to comprise two multisubunit complexes, namely, IFT-A and IFT-B; however, little is known about how the two complexes cooperate to mediate ciliary protein trafficking. We here show that IFT144-IFT122 from IFT-A and IFT88-IFT52 from IFT-B make major contributions to the interface between the two complexes...

Ciliopathies are a wide and heterogeneous group of diseases affecting intraflagellar transport. Among them, Mainzer-Saldino syndrome (MSS) shows phalangeal cone-shaped epiphysis, renal disease and retinal involvement. Short stature, cerebellar ataxia and hepatic fibrosis might also be found. IFT140 is the most commonly reported mutation in MSS. We will report on the case of a patient with a clinical diagnosis of Mainzer-Saldino syndrome due to IFT144 dysfunction. This mutation has not been previously related to MSS but it has been found in other ciliopathies and both syndromic and non-syndromic retinitis pigmentosa...

Tetratricopeptide repeat domain containing 39c (Ttc39c) is expressed in skeletal muscle and is transcriptionally activated in response to neurogenic atrophy in mice. Expression analysis using quantitative polymerase chain reaction and Western blots revealed that Ttc39c is expressed in both proliferating and differentiated muscle cells, peaking during early differentiation and then decreasing as cells progress further through the differentiation process. To further analyze the transcriptional regulation of Ttc39c, promoter fragments of the gene were cloned and fused with the secreted alkaline phosphatase reporter gene...

The intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes mediates ciliary protein trafficking. Mutations in the genes encoding the six subunits of the IFT-A complex (IFT43, IFT121, IFT122, IFT139, IFT140, and IFT144) are known to cause skeletal ciliopathies, including cranioectodermal dysplasia (CED). As the IFT122 subunit connects the core and peripheral subcomplexes of the IFT-A complex, it is expected to play a pivotal role in the complex. Indeed, we here showed that knockout (KO) of the IFT122 gene in hTERT-RPE1 cells using the CRISPR/Cas9 system led to a severe ciliogenesis defect, whereas KO of other IFT-A genes had minor effects on ciliogenesis but impaired ciliary protein trafficking...

Cilia serve as cellular antennae where proteins involved in sensory and developmental signaling, including G protein-coupled receptors (GPCRs), are specifically localized. Intraflagellar transport (IFT)-A and -B complexes mediate retrograde and anterograde ciliary protein trafficking, respectively. Using a visible immunoprecipitation assay to detect protein-protein interactions, we show that the IFT-A complex is divided into a core subcomplex, composed of IFT122/IFT140/IFT144, which is associated with TULP3, and a peripheral subcomplex, composed of IFT43/IFT121/IFT139, where IFT139 is most distally located...

Testis cords, embryonic precursors of the seminiferous tubules, are fundamental for testis structure and function. Delay or disruption of testis cord formation could result in gonadal dysgenesis. Although mechanisms regulating testis cord formation during sex determination have been well-studied, the genes and signaling pathways involving in testis cord maintenance after the cords have formed are not well characterized. It is now clear that the maintenance of cord structure is an active process. In this review, we summarize the recent findings regarding the regulation of testis cord integrity by a series of Sertoli cell transcription factors, including the WT1-SOX8/SOX9-beta-CATENIN-DHH network, GPR56, STIM1, and NR0B1 (also known as DAX1)...

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive ciliary chondrodysplasia characterized by a recognizable craniofacial gestalt, skeletal abnormalities, and ectodermal features. To date, four genes have been shown to underlie the syndrome, namely, IFT122 (WDR10), WDR35 (IFT121), IFT43 (C14orf179), and WDR19 (IFT144). Clinical characterization of a larger cohort of patients with CED has been undertaken previously. Nevertheless, there are too few molecularly confirmed patients reported in the literature to determine precise genotype-phenotype correlations...

The issues of whether and how some organs coordinate their size and shape with the blueprint of the embryo axis, while others appear to regulate their morphogenesis autonomously, remain poorly understood. Mutations in Ift144, encoding a component of the trafficking machinery of primary cilia assembly, result in a range of embryo patterning defects, affecting the limbs, skeleton and neural system. Here, we show that embryos of the mouse mutant Ift144(twt) develop gonads that are larger than wild-type. Investigation of the early patterning of the urogenital ridge revealed that the anterior-posterior domain of the gonad/mesonephros was extended at 10...

BACKGROUND: An emerging number of clinically and genetically heterogeneous diseases now collectively termed ciliopathies have been connected to the dysfunction of primary cilia. We describe an 8-year-old girl with a complex phenotype that did not clearly match any familiar syndrome. CASE-DIAGNOSIS/TREATMENT: Hypotonia, facial dysmorphism and retardation were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure...

Two intraflagellar transport (IFT) complexes, IFT-A and IFT-B, build and maintain primary cilia and are required for activity of the Sonic hedgehog (Shh) pathway. A weak allele of the IFT-A gene, Ift144, caused subtle defects in cilia structure and ectopic activation of the Shh pathway. In contrast, strong loss of IFT-A, caused by either absence of Ift144 or mutations in two IFT-A genes, blocked normal ciliogenesis and decreased Shh signaling. In strong IFT-A mutants, the Shh pathway proteins Gli2, Sufu, and Kif7 localized correctly to cilia tips, suggesting that these pathway components were trafficked by IFT-B...

Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene...

Chlamydomonas reinhardtii intraflagellar transport (IFT) particles can be biochemically resolved into two smaller assemblies, complexes A and B, that contain up to six and 15 protein subunits, respectively. We provide here the proteomic and immunological analyses that verify the identity of all six Chlamydomonas A proteins. Using sucrose density gradient centrifugation and antibody pulldowns, we show that all six A subunits are associated in a 16 S complex in both the cell bodies and flagella. A significant fraction of the cell body IFT43, however, exhibits a much slower sedimentation of ∼2 S and is not associated with the IFT A complex...

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy...

Mediating the transport of flagellar precursors and removal of turnover products, intraflagellar transport (IFT) is required for flagella assembly and maintenance. The IFT apparatus is composed of the anterograde IFT motor kinesin II, the retrograde IFT motor IFT-dynein, and IFT particles containing two complexes, A and B. In order to have a balanced two-way transportation, IFT-dynein has to be carried into flagella and transported to the flagellar tip by kinesin II, where it is activated to drive the retrograde IFT back to the flagellar base...

The nematode Caenorhabditis elegans presents numerous advantages for the identification and molecular analysis of intraflagellar transport (IFT)-associated proteins, which play a critical role in the formation of cilia. Many proteins were first described as participating in IFT in this organism, including IFTA-1 (IFT121), DYF-1 (fleer/IFT70), DYF-2 (IFT144), DYF-3 (Qilin), DYF-11 (MIP-T3/IFT54), DYF-13, XBX-1 (dynein light intermediate chain), XBX-2 (dynein light chain), CHE-13 (IFT57/HIPPI), orthologs of Bardet-Biedl syndrome proteins, and potential regulatory protein, IFTA-2 (RABL5/IFT22)...

The intraflagellar transport machinery is required for the assembly of cilia. It has been investigated by biochemical, genetic, and computational methods that have identified at least 21 proteins that assemble into two subcomplexes. It has been hypothesized that complex A is required for retrograde transport. Temperature-sensitive mutations in FLA15 and FLA17 show defects in retrograde intraflagellar transport (IFT) in Chlamydomonas. We show that IFT144 and IFT139, two complex A proteins, are encoded by FLA15 and FLA17, respectively...