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

• Autorzy: Macias A. , Fichna J. , Korostynski M. , Piechota M. , Potulska-Chromik A. , Redowicz M.J. , Zekanowski C. , Kaminska A.M. , Kostera-Pruszczyk A.
• Języki publikacji: EN

Abstrakty

EN

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.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.71

Twórcy

autor

Macias A.

• Department of Neurology, Medical University of Warsaw, Warsaw, Poland

autor

Fichna J.

• Department of Neurodegenerative Disorders, Mossakowski Medical Research Center Polish Academy of Sciences, Warsaw, Poland

autor

Korostynski M.

• Department of Molecular Neuropharmacology, Institute of Pharmacology Polish Academy of Sciences, Cracow, Poland

autor

Piechota M.

• Department of Molecular Neuropharmacology, Institute of Pharmacology Polish Academy of Sciences, Cracow, Poland

autor

Potulska-Chromik A.

• Department of Neurology, Medical University of Warsaw, Warsaw, Poland

autor

Redowicz M.J.

• Laboratory of Molecular Basis of Cell Motility, Department of Biochemistry, Nencki Institute of Experimental Biology Polish Academy of Sciences, Warsaw, Poland

autor

Zekanowski C.

• Department of Neurodegenerative Disorders, Mossakowski Medical Research Center Polish Academy of Sciences, Warsaw, Poland

autor

Kaminska A.M.

• Department of Neurology, Medical University of Warsaw, Warsaw, Poland

autor

Kostera-Pruszczyk A.

• Department of Neurology, Medical University of Warsaw, Warsaw, Poland