Humans have a highly developed retina and obtain approximately 80% of their external information from vision. Photoreceptor cells, which are located in the outermost layer of the neuroretina and recognize light signals, are highly specialized sensory cilia that share structural and functional features with primary cilia. Genetic disorders of the retina or photoreceptor cells are termed inherited retinal diseases (IRDs) and are caused by variants in one of more than 280 genes identified to date. Among the genes responsible for IRDs, many are shared with those responsible for ciliopathies. In studies of inherited diseases, mouse models are commonly used due to their advantages in breeding, handling, and relative feasibility in creating pathological models. On the other hand, structural, functional, and genetic differences in the retina between mice and humans can be a barrier in IRD research. To overcome the limitations of mouse models, larger vertebrate models of IRDs can be a useful research subject. In particular, canines have retinas that are structurally and functionally similar and eyes that are anatomically comparable to those of humans. In addition, due to their unique veterinary clinical surveillance and genetic background, naturally occurring canine IRDs are more likely to be identified than in other large animals. To date, pathogenic mutations related to canine IRDs have been identified in more than 30 genes, contributing to the understanding of pathogeneses and to the development of new therapies. This review provides an overview of the roles of the canine IRD models in ciliopathy research.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

Cilia and flagella are evolutionarily conserved organelles that form protrusions on the surface of many growth-arrested or differentiated eukaryotic cells. Due to the structural and functional differences, cilia can be roughly classified as motile and non-motile (primary). Genetically determined dysfunction of motile cilia is the basis of primary ciliary dyskinesia (PCD), a heterogeneous ciliopathy affecting respiratory airways, fertility, and laterality. In the face of the still incomplete knowledge of PCD genetics and phenotype-genotype relations in PCD and the spectrum of PCD-like diseases, a continuous search for new causative genes is required. The use of model organisms has been a great part of the advances in understanding molecular mechanisms and the genetic basis of human diseases; the PCD spectrum is not different in this respect. The planarian model (Schmidtea mediterranea) has been intensely used to study regeneration processes, and-in the context of cilia-their evolution, assembly, and role in cell signaling. However, relatively little attention has been paid to the use of this simple and accessible model for studying the genetics of PCD and related diseases. The recent rapid development of the available planarian databases with detailed genomic and functional annotations prompted us to review the potential of the S. mediterranea model for studying human motile ciliopathies.

Primary cilium (PC) is a microtubule-based organelle found on the apical surface of most mammalian cell types, playing a role in development and tissue homeostasis. Ciliopathies are a rapidly growing group of human diseases characterized by disordered cilium. PC plays an important role in pathogenesis of basal cell cancer, the most common human malignancy. A significant increase in ciliation has been observed in the epidermis of atopic dermatitis and psoriasis patients. Spontaneously immortalized human keratinocytes, HaCaT are a model to study the epidermal homeostasis and pathophysiology. In contrast to what has been previously described, here, we show that HaCaT can be efficiently ciliated. In HaCaT cells, differentiation significantly increased the number of ciliated cells and we were able to analyse in detail the ciliary length progression with duration of differentiation. As the number of recognized ciliopathies continues to increase, the importance of ciliary models also rises. Even though keratinocytes do not become as highly and rapidly ciliated as cell lines frequently used in ciliary studies, they are a better model for the study of skin ciliopathies. Detailed progression of ciliation in HaCaT could serve as the basis for ciliary studies in this cell line.

Polycystic kidney diseases (PKD) are severe forms of genetic kidney disorders. The two main types of PKD are autosomal recessive and autosomal dominant PKD (ARPKD, ADPKD). While ARPKD typically is a disorder of early childhood, patients with ADPKD often remain pauci-symptomatic until adulthood even though formation of cysts in the kidney already begins in children. There is clinical and genetic overlap between both entities with very variable clinical courses. Subgroups of very early onset ADPKD may for example clinically resemble ARPKD. The basis of the clinical variability in both forms of PKD is not well understood and there are also limited prediction markers for disease progression for daily clinical life or surrogate endpoints for clinical trials in ARPKD or early ADPKD.As targeted therapeutic approaches to slow disease progression in PKD are emerging, it is becoming more important to reliably identify patients at risk for rapid progression as they might benefit from early therapy. Over the past years regional, national and international data collections to jointly analyze the clinical courses of PKD patients have been set up. The clinical observations are complemented by genetic studies and biorepositories as well as basic science approaches to elucidate the underlying molecular mechanisms in the PKD field. These approaches may serve as a basis for the development of novel therapeutic interventions in specific subgroups of patients. In this article we summarize some of the recent developments in the field with a focus on kidney involvement in PKD during childhood and adolescence and findings obtained in pediatric cohorts.

UNASSIGNED: Primary ciliary dyskinesia (PCD) is characterised by an imbalance in mucociliary clearance leading to chronic respiratory infections. Cilia length is considered to be a contributing factor in cilia movement. Recently, IFT46 protein has been related to cilia length. Therefore, this work aims to study IFT46 expression in a PCD patients cohort and analyse its relationship with cilia length and function, as it was not previously described.
UNASSIGNED: The expression of one intraflagellar transport (IFT46) and two regulating ciliary architecture (FOXJ1 and DNAI2) genes, as well as cilia length of 27 PCD patients, were measured. PCD patients were diagnosed based on clinical data, and cilia function and ultrastructure. Gene expression was estimated by real-time RT-PCR and cilia length by electron microscopy in nasal epithelium biopsies.Results and conclusions: While IFT46 expression was only diminished in patients with short cilia, FOXJ1, and DNAI2 expression were reduced in all PCD patient groups compared to controls levels. Among the PCD patients, cilia were short in 44% (5.9 ± 0.70 µm); nine of these (33% from the total) patients\' cilia also had an abnormal ultrastructure. Cilia length was normal in 33% of patients (6.4 ± 0.39 µm), and only three patients\' biopsies indicated decreased expression of dynein.

The recent application of proteomics and metabolomics to clinical medicine has demonstrated their potential role in complementing genomics for a better understanding of diseases\' patho-physiology. These technologies offer the clear opportunity to identify risk factors, disease-specific or stage-specific biomarkers and to predict therapeutic response. This article is an overview of the recent insights obtained by metabolomic and proteomic studies in inherited kidney disorders. Proteomics studies have allowed the definition of a detailed picture of protein composition, post-translational modifications and interactions in kidney-derived samples, improving our understanding of renal physiology, especially of tubular transport and primary cilium-related functions. Studies on patients\' urine samples and experimental models of inherited kidney diseases have provided clues suggesting novel potential pathological mechanisms and biomarkers of disease, for example in polycystic kidney disease. Metabolomic-based studies have been recently applied to assess biological system disturbances caused by specific genetic mutations resulting in inherited kidney disorders. These studies have been mainly carried out on mouse and rat models of cystic and metabolic disorders (such as Fabry disease), and on patients\' urine samples. They have provided a significant contribution in understanding disease pathophysiology, promoting the discovery of aberrant biochemical pathways and contributing to the development of targeted therapies.

The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms.

Nephronophthisis is an autosomal recessive cystic kidney disease characterized by tubular interstitial infiltration, periglomerular fibrosis, and cysts, and is the most frequent genetic cause of end-stage renal disease in children. Nephronophthisis is pleiotropic as almost all the causative genes are involved in primary cilium and centrosome function which are found in almost all human cells. Genetic heterogeneity in nephronophthisis makes the molecular and genetic diagnosis somewhat difficult. Homozygous deletions in the nephronophthisis 1 (NPHP1) gene are the major contributor of nephronophthisis cases, while other genes accounts for less than 3% each. Nephronophthisis-related ciliopathy is a term used for extrarenal symptoms in addition to nephronophthisis. Herein, we are reporting the molecular study of 7 children from independent families fulfilling the criteria of nephronophthisis. A deletion analysis of the NPHP1 gene was performed in each case, and NPHP5 mutation screening was performed in the absence of such deletion in patients with Senior Loken syndrome.

Cilia are highly-conserved organelles projecting from the cell surface of nearly every cell type in vertebrates. Ciliary proteins have essential functions in human physiology, particularly in signaling and organ development. As cilia are a component of almost all vertebrate cells, cilia dysfunction can manifest as a constellation of features that characteristically include, retinal degeneration, renal disease and cerebral anomalies. The terminology \"Ciliopathies\" refers to inherited human disorders caused by genetic mutations in ciliary genes, leading to cilia dysfunctions that form an important and ever expanding multi-organ disease spectrum. Ciliopathies are a diverse class of congenital diseases, with twenty-four recognized syndromes caused by mutations in at least ninety different genes. In order to start to dissect the phenotypes of each disease associated with ciliary dysfunction it is necessary to understand the mechanisms underlying the phenotype using suitable animal models. Here, we review the advantages of the zebrafish as a vertebrate model for human ciliopathies, with a focus on ciliopathies affecting the eye and the kidney.