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Molecular correlates of joint pain intensity in osteoarthritis

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Mlost J. , Bryk M. , Chwastek J. , Korostynski M. , Starowicz K.

tom Vol. 21, no. 148

107

Let genes talk: transcriptomic changes in the PFC induced by L-DOPA in hemiparkinsonian rats

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Radlicka A. , Kaminska K. , Piechota M. , Korostynski M. , Lorenc-Koci E. , Pera J. , Parkitna J. R.

nr Suppl.1

INTRODUCTION: The hallmark symptoms of Parkinson’s disease (PD) are progressive motor impairments. Nevertheless, PD is also associated with altered executive function and other cognitive impairments. While treatments of PD provide at least temporary relief from the motor symptoms, the effects of L-DOPA on the cognitive impairments may provide mixed effects and require further investigation. AIM(S): Here we assess changes in gene expression in the prefrontal cortex (PFC) of rats with unilateral lesion of midbrain dopamine neurons. METHOD(S): Male Wistar Han rats were infused with 6‑hydroxydopamine (6‑OHDA, 8 µg/4 µl) into the left medial forebrain bundle. The experimental animals were treated i.p. with L‑DOPA (12.5 mg/kg) supplemented with benserazide hydrochloride (6.25 mg/kg) daily for 14 days. An hour after the last dose, the rats were killed, and the left and right PFC were isolated separately. Analysis of gene expression was performed by RNA‑seq (Illumina PE 150, 20M pair reads per sample). Reads were aligned to rn6 rat reference genome using hisat2 2.1.0. RESULTS: We identified 12,459 genes with FPKM > 1 after L‑DOPA treatment in both ipsi‑ and contralateral portions of the PFC of rats lesioned with 6‑OHDA. Two‑way ANOVA revealed 48 genes with differential expression profiles. The effect of treatment was the most pronounced, and included transcripts linked to activity-regulated expression in neurons and metabolism in the glia. Ontology analysis of the genes with altered expression indicated over-representation of terms associated with cytokine and glucocorticoid signalling. The involvement of altered glucocorticoid signalling induced by L-DOPA treatment was also confirmed by analysis of the promoter regions of the regulated genes. CONCLUSIONS: Unilateral lesions of dopamine neurons lead to enhanced sensitization of neurons in PFC to L‑DOPA action. We show that, to a large extent, these changes appear to bilaterally affect the molecular profile of PFC.

FKRP gene mutations and candidate disease-modifying genes in Polish patients with limb-girdle muscular dystrophy – results of whole exome sequencing study

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Macias A. , Fichna J. , Korostynski M. , Piechota M. , Potulska-Chromik A. , Redowicz M. J. , Zekanowski C. , Kaminska A. M. , Kostera-Pruszczyk A.

nr Suppl.1

INTRODUCTION: Limb-girdle muscular dystrophies (LGMD) are hereditary progressive disorders of skeletal muscles. Currently 33 LGMD types are recognized. For up to 50% of LGMD patients the causal genetic defect remains unknown. There is considerable phenotypic variability, even among patients with identical causal mutation. Mutations in fukutin-related protein (FKRP) gene are responsible for an autosomal recessive type 2 I of LGMD, which is a relatively frequent type of LGMD in Europe. AIM(S): The aim of this work was to assess frequency of LGMD2I in Polish LGMD patients, characterize the pathogenic mutations, clinical phenotype and possible disease modifying genes. METHOD(S): The study involved 85 patients with LGMD diagnosis based on clinical assessment and muscle biopsy. Whole exome sequencing of peripheral blood DNA was performed. Filtering of the identified variants was based on allele frequency, association with Human Phenotype Ontology terms and predicted pathogenicity. Selected variants were confirmed using a direct fluorescence‑based sequencing. RESULTS: Homozygous or compound heterozygous mutations in FKRP gene were found in 7/85 patients. L276I mutation was the most common one – found in 6/7 LGMD2I patients, 3 of them were homozygous. We could observe considerable phenotypic variability. Candidate disease-modifying genes were COL6A3, COL12A1, PLEC, SYNE1. In 2 patients with particularly severe course of the disease, heterozygous mutation in genes involved In glycosylation process was found (LARGE, ISPD, ITGA7). Two patients were found to be heterozygous for mutations in DYSF gene. CONCLUSIONS: LGMD2I is a common type of LGMD in Polish population. The most common mutation in FKRP gene is L276I. Heterozygocity for mutations in other LGMD genes is high in this group of patients. New generation sequencing methods are a valuable tool for identifying causal mutations, but also for finding candidate disease‑modifying genes, which can help to elucidate mechanisms of LGMD.