2. Academic Validation
  3. MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs

MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs

  • Ann Neurol. 2016 Mar;79(3):419-27. doi: 10.1002/ana.24575.
Obaid M Albulym 1 2,  Marina L Kennerson 1 2 3,  Matthew B Harms 4,  Alexander P Drew 1 2,  Anna H Siddell 1 2,  Michaela Auer-Grumbach 5,  Alan Pestronk 4,  Anne Connolly 4,  Robert H Baloh 6,  Stephan Zuchner 7,  Stephen W Reddel 1 2 3,  Garth A Nicholson 1 2 3
Affiliations

Affiliations

  • 1 Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.
  • 2 Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
  • 3 Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia.
  • 4 Department of Neurology, Washington University School of Medicine, St Louis, MO.
  • 5 Department of Orthopedics, Medical University of Vienna, Vienna, Austria.
  • 6 Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA.
  • 7 Dr John T. MacDonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL.
PMID: 26659848 DOI: 10.1002/ana.24575
Abstract

Objective: To use linkage analysis and whole exome sequencing to identify the genetic mutation in a multigenerational Australian family with Charcot-Marie-Tooth disease type 2 (CMT2) and pyramidal signs.

Methods: Genome-wide linkage analysis was performed to map the locus. Whole exome sequencing was undertaken on selected individuals (3 affected, 1 normal), and segregation analysis and mutation screening were carried out using high-resolution melt analysis. The GEM.app database was queried to identify additional families with mutations.

Results: Significant linkage (2-point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6Mb interval on chromosome 22q12.1-q12.3. Whole exome sequencing identified a novel mutation (p.R252W) in the microrchidia CW-type zinc finger 2 (MORC2) gene mapping within the linkage region. The mutation fully segregated with the disease phenotype in the family. Screening additional families and querying unsolved CMT2 exomes, we identified the p.R252W mutation in 2 unrelated early onset CMT2 families and a second mutation p.E236G in 2 unrelated CMT2 families. Both the mutations occurred at highly conserved amino acid residues and were absent in the normal population.

Interpretation: We have identified a new locus in which MORC2 mutations are the likely pathogenic cause of CMT2 and pyramidal signs in these families. MORC2 encodes the human CW-type zinc finger 2 protein, which is a chromatin modifier involved in the regulation of DNA repair as well as gene transcription.

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