PubMed Latest Articles

25 June 2022

• De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome
  Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia,...
• Biallelic KIF24 variants are responsible for a spectrum of skeletal disorders ranging from lethal skeletal ciliopathy to severe acromesomelic dysplasia
  Skeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning and homeostasis and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones and metatarsals, and brachydactyly (Family 1); mild...
• CPLANE Complex and Ciliopathies
  Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and...
• A Stargardt disease-like phenotype in GAS8-related primary ciliary dyskinesia
  PURPOSE: Ciliopathies are broadly classified as non-motile or motile (primary ciliary dyskinesia). Early-onset retinal dystrophy is common in non-motile ciliopathy, but retinal dystrophy is not considered a feature of primary ciliary dyskinesia. The subject of this report is woman referred as a case of Stargardt disease who in fact had retinal dystrophy apparently related to GAS8-related primary ciliary dyskinesia.
• Special issue: Cilia and ciliopathies
  No abstract
• Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening
  Primary cilia dyskinesia (PCD) is a rare genetic disease caused by ciliary structural or functional defects. It causes severe outcomes in patients, including recurrent upper and lower airway infections, progressive lung failure, and randomization of heterotaxy. To date, although 50 genes have been shown to be responsible for PCD, the etiology remains elusive. Meanwhile, owing to the lack of a model mimicking the pathogenesis that can be used as a drug screening platform, thereby slowing the...
• Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis
  CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.
• Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report
  Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting the...
• HaCaT cells as a model system to study primary cilia in keratinocytes
  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...
• Research priorities for autosomal dominant polycystic kidney disease: a UK priority setting partnership
  CONCLUSIONS: Our shortlist reflects the varied physical, psychological and practical challenges of living with and treating ADPKD, and perceived gaps in knowledge that impair optimal care. We propose that future ADPKD research funding takes these priorities into account to focus on the most important areas and to maximise improvements in ADPKD outcomes.
• Molecular basis underlying the ciliary defects caused by IFT52 variations found in skeletal ciliopathies
  Bidirectional protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery, which contains the IFT-A and IFT-B complexes powered by the kinesin-2 and dynein-2 motors. Mutations in genes encoding subunits of the IFT-A and dynein-2 complexes cause skeletal ciliopathies. Some subunits of the IFT-B complex, including IFT52, IFT80, and IFT172, are also mutated in skeletal ciliopathies. We here show that IFT52 variants found in individuals with short-rib polydactyly...
• Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B
  CONCLUSIONS: This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.
• A 5-year-old girl with kidney impairment and severe anemia: Answers
  No abstract
• A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
  The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct...
• Zebrafish models of inherited retinal dystrophies
  Inherited retinal degenerations (IRDs) cause permanent vision impairment or vision loss due to the death of rod and cone photoreceptors. Animal models of IRDs have been instrumental in providing knowledge of the pathological mechanisms that cause photoreceptor death and in developing successful approaches that could slow or prevent vision loss. Zebrafish models of IRDs represent an ideal model system to study IRDs in a cone-rich retina and to test strategies that exploit the natural ability to...
• Caroli's disease incidentally discovered in a 16-years-old female: a case report
  Caroli´s disease is a congenital hepatic disorder characterized by nonobstructive saccular or fusiform dilatation of the intrahepatic bile ducts with the absence of congenital hepatic fibrosis. Caroli´s disease is rare, with few reported cases in the literature, making it hard to distinguish from other liver abnormalities. We present a case of Caroli´s disease discovered indecently in a 16-year-old female who presented with recurrent abdominal pain and intermittent jaundice in the last three...
• A combined in silico and in vivo approach to the structure-function annotation of SPD-2 provides mechanistic insight into its functional diversity
  Centrosomes are organelles that function as hubs of microtubule nucleation and organization, with key roles in organelle positioning, asymmetric cell division, ciliogenesis, and signaling. Aberrant centrosome number, structure or function is linked to neurodegenerative diseases, developmental abnormalities, ciliopathies, and tumor development. A major regulator of centrosome biogenesis and function in C. elegans is the conserved Spindle-defective protein 2 (SPD-2), a homolog of the human CEP-192...
• Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects
  Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in...
• Ciliary membrane, localised lipid modification and cilia function
  Cilium, a tiny microtubule-based cellular appendage critical for cell signalling and physiology, displays a large variety of receptors. The composition and turnover of ciliary lipids and receptors determine cell behaviour. Due to the exclusion of ribosomal machinery and limited membrane area, a cilium needs adaptive logistics to actively reconstitute the lipid and receptor compositions during development and differentiation. How is this dynamicity generated? Here, we examine whether, along with...
• The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies
  The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. Primary cilia are near-ubiquitous,...
• Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes
  CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). Depletion of CCDC28B resulted in a mild phenotype. Ccdc28b mut animals i) do not present clear structural cilia affectation, although...