RELN rare variants in myoclonus-dystonia

Mov Disord. 2015 Mar;30(3):415-9. doi: 10.1002/mds.26070. Epub 2015 Feb 4.

Abstract

Background: Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M-D cases are caused by mutations in the epsilon-sarcoglycan gene. In remaining M-D patients, no genetic factor has been established, indicating genetic heterogeneity.

Methods: Patients were included in a prospective clinical database and recruited from referral centers and general neurology clinics in The Netherlands. To investigate new genetic causal factors in M-D syndrome, we performed homozygosity mapping combined with exome sequencing in a three-generation M-D family and genetically screened 24 additional patients with M-D.

Results: We found co-segregation of the rare missense variant Thr1904Met in the RELN gene. By additional screening of an M-D cohort, we identified co-segregation of RELN variants in two families (Thr1904Met, Ile1217Met) and identified two sporadic RELN mutation carriers (Pro1703Arg, Leu411Ile). Taken together, five of 25 SGCE-negative M-D patients carried RELN rare missense variants.

Conclusion: We propose that RELN mutations contribute to the genetic heterogeneity of M-D. Reelin is a large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and modulation of synaptic transmission and plasticity.

Keywords: RELN; genetics; myoclonus-dystonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cohort Studies
  • DNA Mutational Analysis
  • Dystonic Disorders / genetics*
  • Extracellular Matrix Proteins / genetics*
  • Family Health*
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Serine Endopeptidases / genetics*
  • Young Adult

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Serine Endopeptidases
  • reelin protein

Supplementary concepts

  • Myoclonic dystonia