Project description:<p>Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes including <i>POLG1</i> and <i>C10orf2</i>/Twinkle have been identified as responsible genes. On the other hand, <i>POLG1</i> was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected. To identify the disease causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis.</p>
Project description:26 limb-girdle muscular dystrophy patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 204 healthy unrelated controls were genotyped for 96 most frequent known limb-girdle muscular dystrophies causing mutations for the region, using VeraCode GoldenGate system. More information can be found in article Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies in BMC Musculoskeletal Disorders by I. Inashkina et al.
Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurological disease characterized by autosomal recessive mutations in the sacsin gene (SACS), that cause in patients progressive cerebellar atrophy, damage of the peripheral nerves, and significant retinal changes and cognitive impairment. No effective therapies have been proposed for ARSACS, even if some evidences suggest that powerful antioxidant agents can be considered a therapeutic tool. Resveratrol (Res) is a natural polyphenol compound derived from vegetal sources, the application of which in biomedicine is increasing in the latest years because of its significant therapeutic effects, in particular in neurodegenerative diseases. In this study, we provide evidences about its potential exploitation in the treatment of ARSACS. Because of the low solubility of resveratrol in physiological media, a nanoplatform based on nanostructured lipid carriers is here proposed for its encapsulation and delivery. Resveratrol-loaded nanostructured lipid carriers (Res-NLCs) have been synthetized, characterized, and tested on healthy and ARSACS patient fibroblasts. Nanovectors displayed optimal stability and biocompatibility, and excellent antioxidant and anti-inflammatory activities. A comprehensive investigation at gene (with real-time quantitative RT-PCR (qRT-PCR)) and protein (with proteomics) level demonstrated the therapeutic potential of Res-NLCs, encouraging future investigations on pre-clinical models.
Project description:An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient’s gene, it has been challenging to determine which two of the variants are responsible for the disease phenotype. To decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5’ and 3’ variants was around 19 kb at the level of genomic DNA. nCATS successfully delineated that the most 5’ and 3’ variants were located in one allele while the variant in between was in the other allele. Intriguingly, the proband’s mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study illuminates nCATS as a useful tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can tell which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.
Project description:Non-syndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked ones, but in contrast to the latter, they are still largely unexplored. Here we report on a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, GLUR6), which co-segregates with moderate to severe non-syndromic autosomal recessive mental retardation in a large consanguineous Iranian family1. The predicted gene product lacks the first ligand-binding domain, the two adjacent transmembrane domains and the putative pore-forming loop of the GLUK6 protein, suggesting a complete loss of function, which is supported by electrophysiological data. This finding provides the first irrefutable proof that GLUK6 is indispensable for higher brain functions in man, and future studies of this and other ionotropic kainate receptors will shed more light on the pathophysiology of mental retardation. Keywords: array CGH