341 research outputs found
Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: a case report and literature review
No full textBackground: Mutations in proteins involved in the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway are associated with autosomal recessive forms of intellectual disability. Recently mutations in the PGAP1 gene that codes for PGAP1, a protein localized in the endoplasmic reticulum responsible for the first step of the remodeling of glycosylphosphatidylinositol was linked to a disorder characterized by psychomotor retardation and facial dysmorphism. Whole exome sequencing (WES) was performed in siblings with severely delayed myelination and psychomotor retardation. Mutations in PGAP1 were confirmed by Sanger sequencing and RNA analysis. A literature search was performed to describe the emerging phenotype of PGAP1 related disease. Case presentation: WES resulted in the detection of two novel compound heterozygous mutations in PGAP1, one base pair insertion leading to a frame shift c.334_335InsA (p.A112fs) and a splice site mutation leading to exon skipping c.G1173C (p.L391L). A symptom not described in PGAP1 related disorder before but prominent in the siblings were recurrent apnea especially during sleep that persisted at least until age 2 years. Sequential cerebral MRI at age one and two year(s) respectively revealed frontal accentuated brain atrophy and significantly delayed myelination. Conclusion: We report siblings with two novel mutations in PGAP1. Other that the common symptoms related to PGAP1 mutations including non-progressive psychomotor retardation, neonatal feeding problems, microcephaly and brain atrophy these patients displayed severely delayed myelination and recurrent apneas thereby widing the clinical spectrum associated with such mutations
Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome
No full textRett syndrome (RTT), a severe X-linked neurodevelopmental disorder, is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). Over 35% RTT patients carry nonsense mutation in MECP2, making it a suitable candidate disease for nonsense suppression therapy. In our previous study, gentamicin was found to induce readthrough of MECP2 nonsense mutations with modest efficiency. Given the recent discovery of readthrough enhancers, CDX compounds, we herein evaluated the potentiation effect of CDX5-1, CDX5-288, and CDX6-180 on gentamicin-mediated readthrough efficiency in transfected HeLa cell lines bearing the four most common MECP2 nonsense mutations. We showed that all three CDX compounds potentiated gentamicin-mediated readthrough and increased full-length MeCP2 protein levels in cells expressing the R168X, R255X, R270X, and R294X nonsense mutations. Among all three CDX compounds, CDX5-288 was the most potent enhancer and enabled the use of reduced doses of gentamicin, thus mitigating the toxicity. Furthermore, we successfully demonstrated the upregulation of full-length Mecp2 protein expression in fibroblasts derived from Mecp2R255X/Y mice through combinatorial treatment. Taken together, findings demonstrate the feasibility of this combinatorial approach to nonsense suppression therapy for a subset of RTT patients.Medicine, Faculty ofNon UBCBiochemistry and Molecular Biology, Department ofReviewedFacultyResearche
Characterization of the MeCP2R168X knockin mouse model for Rett syndrome.
No full textRett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2(R168X) mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2(R168X) mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging
Tectonic gene mutations in patients with Joubert syndrome
No full textSo far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with Meckel-Gruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients
sj-pdf-1-wso-10.1177_17474930231180434 – Supplemental material for No-reflow phenomenon in stroke patients: A systematic literature review and meta-analysis of clinical data
No full textSupplemental material, sj-pdf-1-wso-10.1177_17474930231180434 for No-reflow phenomenon in stroke patients: A systematic literature review and meta-analysis of clinical data by Adnan Mujanovic, Felix Ng, Thomas R Meinel, Tomas Dobrocky, Eike I Piechowiak, Christoph C Kurmann, David J Seiffge, Susanne Wegener, Roland Wiest, Lukas Meyer, Jens Fiehler, Jean Marc Olivot, Marc Ribo, Thanh N Nguyen, Jan Gralla, Bruce CV Campbell, Urs Fischer and Johannes Kaesmacher in International Journal of Stroke</p
Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model (vol 89, pg 389, 2011)
No full textReadthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model
No full textThirty-five percent of patients with Rett syndrome carry nonsense mutations in the MECP2 gene. We have recently shown in transfected HeLa cells that readthrough of nonsense mutations in the MECP2 gene can be achieved by treatment with gentamicin and geneticin. This study was performed to test if readthrough can also be achieved in cells endogenously expressing mutant MeCP2 and to evaluate potentially more effective readthrough compounds. A mouse model was generated carrying the R168X mutation in the MECP2 gene. Transfected HeLa cells expressing mutated MeCP2 fusion proteins and mouse ear fibroblasts isolated from the new mouse model were treated with gentamicin and the novel aminoglycosides NB30, NB54, and NB84. The localization of the readthrough product was tested by immunofluorescence. Read-through of the R168X mutation in mouse ear fibroblasts using gentamicin was detected but at lower level than in HeLa cells. As expected, the readthrough product, full-length Mecp2 protein, was located in the nucleus. NB54 and NB84 induced readthrough more effectively than gentamicin, while NB30 was less effective. Readthrough of nonsense mutations can be achieved not only in transfected HeLa cells but also in fibroblasts of the newly generated Mecp2(R168X) mouse model. NB54 and NB84 were more effective than gentamicin and are therefore promising candidates for readthrough therapy in Rett syndrome patients
A Grammar of Savosavo
No full textWegener C. A Grammar of Savosavo. Mouton Grammar Library. Vol 61. Berlin, New York: Mouton de Gruyter; 2012.This is the first comprehensive description of Savosavo, a non-Austronesian (Papuan) language spoken by approximately 2,500 speakers on Savo Island, Solomon Islands. Based on primary field data recorded by the author, it provides an overview of all levels of grammar. In addition, a full chapter is dedicated to nominalization of verbs by means of one particular suffix, which occur in a number of constructions ranging from lexical to syntactic nominalization. The appendix provides glossed example texts and a list of lexemes
Adhesion of liposomes: A quartz crystal microbalance study.
No full textThree different systems are presented, exploring the adhesion of liposomes mediated by electrostatic and lipid-protein interactions as well as molecular recognition of ligand receptor pairs. Liposomes are frequently used to gain insight into the complicated processes involving adhesion and subsequent events such as fusion and fission mainly triggered by specific proteins. We combined liposome technology with the quartz crystal microbalance (QCM) technique as a powerful tool to study the hidden interface between the membrane and functionalized surface. Electrostatic attraction and molecular recognition were employed to bind liposomes to the functionalized quartz crystal. The QCM was used to distinguish between adsorption of vesicles and rupture due to strong adhesive forces. Intact vesicles display viscoelastic behaviour, while planar lipid bilayers as a result of vesicle rupture can be modelled by a thin rigid film. Furthermore, the adhesion of cells was modelled successfully by receptor bearing liposomes. Scanning force microscopy was used to confirm the results obtained by QCM measurements
Regional aspects of decision-making support for rural development in Poland
No full textMeasures for rural development should be adapted to the specific regional conditions and national programs should allow for different regional priorities. However, decision-making for policy measures often takes place under special conditions with many concerned actors, unstructured decision problems and time pressure. These conditions, decision-makers in administrations and institutions are faced with, make the formation of policy-measures for rural development a complex matter. Thus, there is the question arising how decision-makers can be supported in setting priorities for allocating budgets for policy measures among regions. Recently, multi criteria decision-making approaches are discussed to tackle these kinds of decision problems. We show exemplarily for the Polish program of rural development, how decision-making could be supported using a multi-objective programming approach. Different preferences of actors can be considered explicitly by visualizing “trade-offs” and an interactive use of the approach. For example, a political "equity" objective is implemented as a constraint in the programming approach, restricting the budget differences between regions to a defined level. By a parameterization of the bound for budget differences, the "trade-off" between three objectives is displayed and evaluated. Using the exemplary programming approach, it is shown that the objective values of the two main objectives of the PROW decline, when the budget differences between regions are restricted for pursuing a political "equity" objective.Regional Budgeting, Interactive Decision-making support, Multi-objective Programming (MOP), Community/Rural/Urban Development,
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