Search Results (168)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA–B-Raf–MEK–ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD’s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD. Full article

Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential role in sperm flagellum biogenesis, but the precise mechanisms underlying this role remain unclear. Serologically defined colon cancer autoantigen protein 8 (SDCCAG8), which encodes a protein containing eight coiled-coil (CC) domains, has been associated with syndromic ciliopathies and male infertility. However, its exact role in male infertility remains undefined. Here, we used an Sdccag8 mutant mouse carrying a CC domains 5–8 truncated mutation (c.1351–1352insG p.E451GfsX467) that models the mutation causing Senior–Løken syndrome (c.1339–1340insG p.E447GfsX463) in humans. The homozygous Sdccag8 mutant mice exhibit male infertility characterized by multiple morphological abnormalities of the flagella (MMAF) and dysmorphic structures in the sperm manchette. A mechanistic study revealed that the SDCCAG8 protein is localized to the manchette and centrosomal region and interacts with PCM1, the scaffold protein of centriolar satellites, through its CC domains 5–7. The absence of the CC domains 5–7 in mutant spermatids destabilizes PCM1, which fails to recruit satellite components such as Bardet–Biedl syndrome 4 (BBS4) and centrosomal protein of 131 kDa (CEP131) to satellites, resulting in defective sperm flagellum biogenesis, as BBS4 and CEP131 are essential to flagellum biogenesis. In conclusion, this study reveals the central role of SDCCAG8 in maintaining centriolar satellite integrity during sperm flagellum biogenesis. Full article

Centriole duplication is a vital process for cellular organisation and function, underpinning essential activities such as cell division, microtubule organisation and ciliogenesis. This review summarises the latest research on the mechanisms and regulatory pathways that control this process, focusing on important proteins such as polo-like kinase 4 (PLK4), SCL/TAL1 interrupting locus (STIL) and spindle assembly abnormal protein 6 (SAS-6). This study examines the complex steps involved in semi-conservative duplication, from initiation in the G1–S phase to the maturation of centrioles during the cell cycle. Additionally, we will explore the consequences of dysregulated centriole duplication. Dysregulation of this process can lead to centrosome amplification and subsequent chromosomal instability. These factors are implicated in several cancers and developmental disorders. By integrating recent study findings, this review emphasises the importance of centriole duplication in maintaining cellular homeostasis and its potential as a therapeutic target in disease contexts. The presented findings aim to provide a fundamental understanding that may inform future research directions and clinical interventions related to centriole biology. Full article

Sensenbrenner syndrome, or cranioectodermal dysplasia (CED), is a rare autosomal recessive ciliopathy characterized by craniofacial, skeletal, ectodermal, and renal abnormalities. Ocular involvement, though infrequent, can include retinal dystrophy with early-onset visual impairment. We report a case of a 2-year-old boy with classic clinical features of CED and significant ocular findings. Genetic testing revealed two novel compound heterozygous variants in the WDR19 gene—c.1778G>T and c.3536T>G—expanding the known mutational spectrum associated with this condition. Ophthalmologic evaluation demonstrated bilateral optic nerve hypoplasia, high hyperopia, and severely reduced ERG responses, consistent with global retinal dysfunction. Fundoscopy revealed optic disk pallor, vessel attenuation, and peripheral pigment changes. Multisystem findings included postaxial polydactyly, brachydactyly, short stature, hypotonia, and stage 2 chronic kidney disease. This case highlights the importance of early ophthalmologic screening in suspected CED and underscores the utility of ERG in detecting early retinal involvement. The identification of two previously undescribed WDR19 variants contributes to genotype–phenotype correlation in CED and emphasizes the need for ongoing documentation to guide diagnosis, management, and genetic counseling. Full article

Bardet–Biedl syndrome (BBS) is a rare multisystem ciliopathy characterized by early-onset retinal degeneration and other vision-threatening ophthalmologic manifestations. This review synthesizes current knowledge on the ocular phenotype of BBS as well as emerging therapeutic approaches aimed at preserving visual function. Retinal degeneration, particularly early macular involvement and rod–cone dystrophy, remains the hallmark of BBS-related vision loss. Additional ocular manifestations, such as refractive errors, nystagmus, optic nerve abnormalities, and cataracts further contribute to visual morbidity. Experimental therapies—including gene-based interventions and pharmacologic strategies such as nonsense suppression and antioxidant approaches—have shown promise in preclinical models but require further validation. Early ophthalmologic care, including routine visual assessments, refractive correction, and low-vision rehabilitation, remains the standard of management. However, there are currently no effective therapies to halt or reverse retinal degeneration, which underscores the importance of emerging molecular and genetic interventions. Timely recognition and comprehensive ophthalmologic evaluation are essential to mitigate visual decline in BBS. Future efforts should focus on translating these approaches into clinical practice, enhancing early diagnosis, and promoting multidisciplinary collaboration to improve long-term outcomes for patients with BBS. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essential for the assembly of outer dynein arms (ODA), with chaperones like Glucose-regulated protein 78 (GRP78) facilitating protein folding. This study investigates ZMYND10 and Dynein axonemal heavy chain 5 (DNAH5) mutations in individuals with PCD. Methods: Eight individuals aged 14–22 with clinical PCD symptoms and confirmed DNAH5 mutations were included. We analyzed the correlation between DNAH5 abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (DNAH5–β-tubulin, β-tubulin–ZMYND10, β-tubulin–GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of DNAH5, ZMYND10, and GRP78 were significantly different between PCD individuals and controls. Metabolomic analysis showed reduced valine, leucine, and isoleucine biosynthesis, with increased malate and triacylglycerol biosynthesis, malate-aspartate and glycerol phosphate shuttles, and arginine/proline metabolism, suggesting mitochondrial and ER stress. Conclusions: The altered expression of DNAH5, ZMYND10, and GRP78, along with metabolic shifts, points to a complex link between ciliary dysfunction and cellular stress in PCD. Further studies are needed to clarify the underlying mechanisms. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental impairment that occurs due to mutations related to the formation of the nervous system, combined with the impact of various epigenetic and environmental factors. This necessitates the identification of the genetic variations involved in ASD pathogenesis. We performed whole exome sequencing (WES) in a cohort of 22 Bulgarian male and female individuals showing ASD features alongside segregation analyses of their families. A targeted panel of genes was chosen and analyzed for each case, based on a detailed examination of clinical data. Gene analyses revealed that specific variants concern key neurobiological processes involving neuronal architecture, development, and function. These variants occur in a number of genes, including SHANK3, DLG3, NALCN, and PACS2 which are critical for synaptic signaling imbalance, CEP120 and BBS5 for ciliopathies, SPTAN1 for spectrins structure, SPATA5, TRAK1, and VPS13B for neuronal organelles trafficking and integrity, TAF6, SMARCB1, DDX3X, MECP2, and SETD1A for gene expression, CDK13 for cell cycle control, ALDH5A1, DPYD, FH, and PDHX for mitochondrial function, and PQBP1, HUWE1, and WDR45 for neuron homeostasis. Novel single nucleotide variants in the SPATA5, CEP120, BBS5, SETD1A, TRAK1, VPS13B, and DDX3X genes have been identified and proposed for use in ASD diagnostics. Our data contribute to a better understanding of the complex neurobiological features of autism and are applicable in the diagnosis and development of personalized therapeutic approaches. Full article

Endocannabinoid signaling plays a significant role in neurogenesis and nervous system physiology, but its roles in the development of other tissues are just beginning to be appreciated. Previous reports have shown the presence of the key endocannabinoid receptor Cannabinoid receptor 1 (CB1 or Cnr1) in multiciliated (MCC) tissues and its upregulation in kidney diseases, yet the relationship between Cnr1 and renal MCC development is unknown. Here, we report that Cnr1 is essential for cilia development across tissues and regulates renal MCCs via cyclic AMP (cAMP) signaling during zebrafish embryogenesis. Using a combination of genetic and pharmacological studies, we found that the loss of function, agonism and antagonism of cnr1 all lead to reduced mature renal MCC populations. cnr1 deficiency also led to reduced cilia development across tissues, including the pronephros, ear, Kupffer’s vesicle (KV), and nasal placode. Interestingly, treatment with the cAMP activator Forskolin (FSK) restored renal MCC defects in agonist-treated embryos, suggesting that cnr1 mediates cAMP signaling in renal MCC development. Meanwhile, treatment with the cAMP inhibitor SQ-22536 alone or with cnr1 deficiency led to reduced MCC populations, suggesting that cnr1 also mediates renal MCC development independently of cAMP signaling. Our findings indicate that cnr1 has a critical role in controlling renal MCC development both via cAMP signaling and an independent pathway, further revealing implications for ciliopathies and renal diseases. Full article

Meckel–Gruber syndrome (MKS) is a rare autosomal recessive lethal ciliopathy, characterized by occipital encephalocele, cystic kidneys, and postaxial polydactyly, caused by mutations in different genes. Its significant genetic heterogeneity along with its clinical overlap with other ciliopathies makes early diagnosis essential for clinical management, accurate genetic counseling, and informing future reproductive decisions. Objectives: This study aims to describe a prenatally diagnosed case carrying a homozygous B9D1 variant and to examine the current literature on all variants reported in this gene associated with MKS. Methods: We comprehensively review the current literature on pathogenic B9D1 variants implicated in this syndrome. Additionally, we describe a case, presenting multiple congenital anomalies suggestive of MKS, genetically diagnosed by clinical exome sequencing on chorionic villi. Results: Occipital encephalocele and polycystic kidneys were revealed via ultrasound, thus suggesting MKS. Genetic testing identified the homozygous c.151T>C (p.Ser51Pro) variant in the B9D1 gene, inherited from healthy parents. Conclusions: This case supports the pathogenicity of the homozygous B9D1 c.151T>C variant and underscores the importance of timely prenatal assessment and targeted genetic testing for the detection of MKS risk in heterozygous subjects, enabling appropriate pregnancy management and informed reproductive choices. Full article

Polycystic kidney disease (PKD), a ciliopathy caused primarily by mutations in the Pkd1 and Pkd2 genes, disrupts renal structure and function, leading to progressive renal failure. The primary cilium, a sensory organelle essential for cellular signaling, plays a pivotal role in maintaining renal function. Among its signaling components, G-protein-coupled receptors (GPCRs) within the cilium have gained significant attention for their localized functions and their contribution to PKD pathogenesis. Dysfunction of ciliary GPCR signaling alters key downstream pathways, including mammalian target of rapamycin (mTOR), cyclic adenosine monophosphate (cAMP), and calcium homeostasis, exacerbating cyst formation and disease progression. Additionally, interactions between ciliary GPCRs and PKD-associated proteins, such as Polycystin-1 (PC1) and Polycystin-2 (PC2), underline the complexity of PKD mechanisms. Recent advances highlight GPCRs as promising therapeutic targets for ciliopathies, including PKD. Emerging GPCR modulators and drugs in clinical trials show the potential to restore ciliary signaling and attenuate disease progression. This paper explores the physiological functions of ciliary GPCRs, their mechanistic links to PKD, and the therapeutic implications of targeting these receptors, offering insights into future research directions and therapeutic strategies for PKD. Full article

Background and Objective: Primary ciliary dyskinesia (PCD) is a rare genetic disorder that affects the mucociliary system, leading to progressive lung damage. This deterioration can result in bronchiectasis, atelectasis, and respiratory failure, necessitating lung transplantation in severe cases. This study aims to assess ciliary motility and ultrastructure in the bronchial epithelium of transplanted lungs in patients with PCD to determine whether mucociliary function is preserved post-transplantation. The findings seek to enhance scientific understanding and provide prognostic insights for these patients. Materials and Methods: A prospective observational study was conducted on two patients with PCD and advanced lung disease who underwent bilateral lung transplantation. Nasal and bronchial cilia samples were analyzed using high-speed videomicroscopy and transmission electron microscopy. Follow-up assessments included ciliary function analysis, lung rejection monitoring, and quality-of-life evaluations, with follow-up extending up to 30 months post-transplant. Results: Post-transplant evaluations demonstrated normal ciliary motility and ultrastructure in the transplanted lungs throughout the study period (up to 30 months), indicating the long-term preservation of mucociliary function. Conclusions: Transplanted lungs in patients with PCD maintain normal bronchial ciliary motility and structure in the long term, suggesting a favorable prognosis for both the graft and the recipient. These findings support the feasibility and long-term effectiveness of lung transplantation in patients with PCD. Full article

Senior–Loken syndrome (SLSN) is a group of rare autosomal recessive disorders caused by dysfunction of the primary cilium, primarily affecting the kidneys (typically leading to nephronophthisis) and eyes (typically leading to retinal degeneration). Moreover, patients with SLSN may experience additional multisystemic symptoms, such as developmental delay, intellectual disability, ataxia, and nystagmus. To date, eight genes have been demonstrated to cause SLSN, all encoding for proteins involved in the structure and functions of the primary cilium. This places SLSN within an expanding category of diseases known as “ciliopathies”. Due to the genetic heterogeneity and significant phenotypic overlap with other ciliopathies, establishing a definitive diagnosis during the initial consultation remains a challenge for clinicians. Furthermore, current research on SLSN-related ciliopathies predominantly focuses on renal involvement, while the ocular manifestations remain insufficiently explored and lack a comprehensive review. Therefore, with the goal of offering practical guidance for clinical practice, this review aims to provide a comprehensive overview of the clinical features, along with an ocular perspective on the molecular mechanisms, genetic underpinnings, and advances in the treatment of SLSN. Full article

Background: Joubert syndrome (JS) is a multi-systemic ciliopathy, characterized by intellectual disability and congenital anomalies involving the brain, kidney, heart, and eye. Even if clinical presentation is variable, most authors consider a brain abnormality known as the molar tooth sign (MTS) as mandatory for diagnosis. About 40 genes were identified to be associated with JS, usually with an autosomal recessive pattern. KATNIP variants represent a rare cause of JS; only six families were previously reported. Methods: We performed exome sequencing in a child with a syndromic phenotype, described the clinical features and molecular findings, and performed a review of the literature to identify known individuals with pathogenic variants in KATNIP, highlighting clinical characteristics and gene-phenotype correlations. Results: Using exome sequencing, we identified a homozygous novel frameshift variant c.808del, p.Ser270ValfsTer28 in KATNIP in a 5-year-old male from a consanguineous family of Roma ethnic background. Notable clinical features of the proband include severe developmental delay, hypotonia, and post-axial polydactyly. He did not have MTS, but showed severe anemia and esophageal atresia, which was already reported in association with a KATNIP variant. We collected the phenotypes of all reported patients and discussed common and distinct features with respect to typical JS. Affected individuals shared JS clinical features, although the typical MTS was not always present, polydactyly and renal abnormalities were absent, while pituitary abnormalities were common. Conclusions: Our report provides new data for KATNIP-related JS, expanding the clinical phenotypic spectrum and suggesting a possible role of KATNIP defects in the development of esophageal atresia. Full article

Background and Clinical Significance: Joubert syndrome (OMIM #213300) is a rare predominantly autosomal recessive inherited condition characterized by the classic cerebellar vermis hypoplasia and brainstem anomalies (also known as the “molar tooth sign”), hypotonia, and developmental delays. Joubert syndrome is a ciliopathy that affects multiple systems including the central nervous system, eyes, kidneys, liver, respiratory, musculoskeletal system, cardiovascular system, and endocrine system. Endocrine abnormalities are not uncommon in Joubert syndrome, such as growth hormone deficiency, thyroid hormone deficiency, central diabetes insipidus, hypopituitarism, micropenis, and obesity. However, a new-onset type 1 diabetes in childhood is not common in Joubert syndrome. Case Presentation: Herein, we report a case of a 7-year-old male with a history of Joubert syndrome presenting with polydipsia, polyuria, weight loss, and hyperglycemia who was diagnosed with type 1 diabetes. Conclusions: While diabetes has been reported as a rare complication in Joubert syndrome, this is the first case report of Joubert syndrome to accentuate new-onset type 1 diabetes as an endocrine complication. Full article

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, affecting approximately 1 in 1000 individuals. This genetically heterogeneous condition is primarily caused by monoallelic pathogenic or likely pathogenic variants in the PKD1 and PKD2 genes, accounting for 78% and 15% of typical cases, respectively. Recently, the application of NGS methods has led to the identification of additional genes associated with ADPKD, which have been incorporated into routine diagnostic testing for detecting phenocopies of the disease. Methods: In this study, targeted NGS (tNGS) analysis of the main cystogenes associated with classic and atypical ADPKD was performed in a cohort of 218 patients clinically diagnosed with cystic nephropathies. Results: Genetic testing identified variants in 175 out of 218 cases (80.3%). Among these, 133 probands (76%) harbored likely pathogenic or pathogenic variants in one or more genes of the panel, while 42 individuals (24%) had a variant of unknown significance (VUS). Specifically, one or more class 4/5 variants in PKD1, PKD2, or both were identified in 111 (83.5%) probands. Remarkably, a pathogenic variant in the IFT140 gene was identified in 14 index cases (8% of positive individuals, 6.4% of the global cohort): 10 distinct loss-of-function (LoF) variants were identified (including four frameshift variants, four nonsense variants, and two splice site defects); one individual carried a second IFT140 missense variant classified as VUS. Furthermore, five affected family members were found to carry a P/LP LoF variant in IFT140. Conclusions: Our data support that IFT140 heterozygous IFT140 LoF variants result in an atypical, mild form of ADPKD, consisting of bilateral kidney cysts and renal functional decline at older ages. Furthermore, we describe the second pediatric patient with a mild form of ADPKD due to an IFT140 variant and discuss hyperuricemia as a previously unappreciated feature of this condition. Full article