RESUMO
Since most short-rib polydactyly phenotypes are due to genes involved with biogenesis and maintenance of the primary cilium, this group of skeletal dysplasias was recently designated as ciliopathies with major skeletal involvement. Beemer-Langer syndrome or short-rib polydactyly type IV, was first described in 1983, and has, thus far, remained without a defined molecular basis. The most recent classification of the skeletal dysplasias referred to this phenotype as an as-yet unproven ciliopathy. IFT122 is a gene that encodes a protein responsible for the retrograde transport along the cilium; it has been associated with this group of skeletal dysplasias. To date, mutations in this gene were only found in Sensenbrenner syndrome. Using a panel of skeletal dysplasias genes, including 11 related to SRP, we identified biallelic mutations in IFT122 ([c.3184G>C];[c.3228dupG;c.3231_3233delCAT]) in a fetus with a typical phenotype of SRP-IV, finally confirmed that this phenotype is a ciliopathy and adding to the list of ciliopathies with major skeletal involvement.
Assuntos
Ciliopatias/genética , Polidactilia/genética , Proteínas/genética , Síndrome de Costela Curta e Polidactilia/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Osso e Ossos/anormalidades , Osso e Ossos/fisiopatologia , Ciliopatias/fisiopatologia , Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Proteínas do Citoesqueleto , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , Feto , Humanos , Recém-Nascido , Mutação , Polidactilia/fisiopatologia , Síndrome de Costela Curta e Polidactilia/fisiopatologiaRESUMO
ã We report on an infant with Opitz trigonocephaly C syndrome (OTCS), who also had manifestations of ciliopathy, including short ribs (non-asphyxiating), trident acetabular roofs, postaxial polydactyly cone-shaped epiphyses, and dysplasia of the renal, hepatic and pancreatic tissues. To investigate the molecular cause, we used an exome sequencing strategy followed by Sanger sequencing. Two rare variants, both predicted to result in loss of functional protein, were identified in the IFT140 gene; a substitution at the splice donor site of exon 24 (c.723 + 1 G > T) and a 17 bp deletion, impacting the first coding exon (c.-11_6del). The variants were confirmed as being biallelic using Sanger sequencing, showing that the splice variant was inherited from the propositus mother and the deletion from the father. To date, Mainzer-Saldino syndrome, Jeune syndrome, and a form of nonsyndromic retinal dystrophy, have been identified as ciliopathies caused by IFT140 mutations. We provide the first description of an OTCS phenotype that appears to result from IFT140 mutations. The presentation of this patient is consistent with previous reports showing that OTCS already exhibited skeleletal and nonskeletal features of a ciliopathy.
Assuntos
Proteínas de Transporte/genética , Ciliopatias/genética , Craniossinostoses/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Ciliopatias/diagnóstico , Ciliopatias/fisiopatologia , Craniossinostoses/diagnóstico , Craniossinostoses/fisiopatologia , Exoma/genética , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Linhagem , Sítios de Splice de RNA/genética , Deleção de Sequência/genéticaRESUMO
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. To date, biallelic IFT122 mutations have been described in only five families. We therefore studied three unrelated Argentinian patients with typical features of CED using a 4813 next-generation sequencing (NGS) gene panel, which we call the "Mendeliome." The three patients had different, novel, compound heterozygous mutations in IFT122. Consequently, we compared these three patients to those previously described with IFT122 mutations. Thus, our report serves to add 6 novel mutations to the IFT122 mutation spectrum and to contribute to the IFT122-related clinical characterization.
Assuntos
Osso e Ossos/anormalidades , Craniossinostoses/genética , Displasia Ectodérmica/genética , Mutação , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Argentina , Osso e Ossos/fisiopatologia , Criança , Craniossinostoses/fisiopatologia , Proteínas do Citoesqueleto , Displasia Ectodérmica/fisiopatologia , Feminino , Humanos , Lactente , MasculinoRESUMO
The flagellar cytoskeleton of Leishmania promastigotes contains the canonical 9+2 microtubular axoneme and a filamentous structure, the paraflagellar rod (PFR), which is present alongside the axoneme. In contrast to promastigotes, which contain a long and motile flagellum, the amastigote form of Leishmania displays a short flagellum without a PFR that is limited to the flagellar pocket domain. Here, we investigated the biogenesis of the Leishmania flagellum at 0, 4, 6 and 24h of differentiation. Light and electron microscopy observations of the early stages of L. amazonensis differentiation showed that the intermediate forms presented a short and wider flagellum that did not contain a PFR and presented reduced motion. 3D-reconstruction analysis of electron tomograms revealed the presence of vesicles and electron-dense aggregates at the tip of the short flagellum. In the course of differentiation, cells were able to adhere and proliferate with a doubling time of about 6h. The new flagellum emerged from the flagellar pocket around 4h after initiation of cell cycle. Close contact between the flagellar membrane and the flagellar pocket membrane was evident in the intermediate forms. At a later stage of differentiation, intermediate cells exhibited a longer flagellum (shorter than in promastigotes) that contained a PFR and electron dense aggregates in the flagellar matrix. In some cells, PFR profiles were observed inside the flagellar pocket. Taken together, these data contribute to the understanding of flagellum biogenesis and organisation during L. amazonensis differentiation.