RESUMEN
Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syndrome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedgehog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies.
Asunto(s)
Proteínas de Ciclo Celular/genética , Centrosoma/metabolismo , Cilios/patología , Proteínas Asociadas a Microtúbulos/genética , Mutación , Fenotipo , Anomalías Múltiples , Enfermedades Cerebelosas/genética , Cerebelo/anomalías , Niño , Cilios/genética , Trastornos de la Motilidad Ciliar/genética , Consanguinidad , Encefalocele/genética , Anomalías del Ojo/genética , Femenino , Homocigoto , Humanos , Lactante , Enfermedades Renales Quísticas/genética , Masculino , Linaje , Enfermedades Renales Poliquísticas/genética , Retina/anomalías , Retinitis Pigmentosa , Transducción de SeñalRESUMEN
Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella-infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.
Asunto(s)
Bacteriófagos/fisiología , Infecciones por Klebsiella/terapia , Klebsiella/virología , Terapia de Fagos , Animales , Bacteriófagos/clasificación , Bacteriófagos/genética , Bacteriófagos/aislamiento & purificación , Biodiversidad , Humanos , Klebsiella/fisiología , Infecciones por Klebsiella/microbiologíaRESUMEN
The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Asunto(s)
Dineínas/genética , Síndrome de Ellis-Van Creveld/genética , Flagelos/fisiología , Animales , Chlamydomonas reinhardtii , Proteínas del Citoesqueleto , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Ratones , Mutación , Penetrancia , Pez CebraRESUMEN
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.