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

Obaid M. Albulym, Marina L. Kennerson, Matthew B. Harms, Alexander P. Drew, Anna H. Siddell, Michaela Auer-Grumbach, Alan Pestronk, Anne Connolly, Robert H. Baloh, Stephan L Zuchner, Stephen W. Reddel, Garth A. Nicholson

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)419-427
Number of pages9
JournalAnnals of Neurology
Volume79
Issue number3
DOIs
StatePublished - Mar 1 2016

Fingerprint

Charcot-Marie-Tooth Disease
Zinc Fingers
Mutation
Exome
Chromosome Mapping
DNA Repair
Haplotypes
Chromatin
Chromosomes
Genome
Databases
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Albulym, O. M., Kennerson, M. L., Harms, M. B., Drew, A. P., Siddell, A. H., Auer-Grumbach, M., ... Nicholson, G. A. (2016). MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. Annals of Neurology, 79(3), 419-427. https://doi.org/10.1002/ana.24575

MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. / Albulym, Obaid M.; Kennerson, Marina L.; Harms, Matthew B.; Drew, Alexander P.; Siddell, Anna H.; Auer-Grumbach, Michaela; Pestronk, Alan; Connolly, Anne; Baloh, Robert H.; Zuchner, Stephan L; Reddel, Stephen W.; Nicholson, Garth A.

In: Annals of Neurology, Vol. 79, No. 3, 01.03.2016, p. 419-427.

Research output: Contribution to journalArticle

Albulym, OM, Kennerson, ML, Harms, MB, Drew, AP, Siddell, AH, Auer-Grumbach, M, Pestronk, A, Connolly, A, Baloh, RH, Zuchner, SL, Reddel, SW & Nicholson, GA 2016, 'MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs', Annals of Neurology, vol. 79, no. 3, pp. 419-427. https://doi.org/10.1002/ana.24575
Albulym OM, Kennerson ML, Harms MB, Drew AP, Siddell AH, Auer-Grumbach M et al. MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. Annals of Neurology. 2016 Mar 1;79(3):419-427. https://doi.org/10.1002/ana.24575
Albulym, Obaid M. ; Kennerson, Marina L. ; Harms, Matthew B. ; Drew, Alexander P. ; Siddell, Anna H. ; Auer-Grumbach, Michaela ; Pestronk, Alan ; Connolly, Anne ; Baloh, Robert H. ; Zuchner, Stephan L ; Reddel, Stephen W. ; Nicholson, Garth A. / MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. In: Annals of Neurology. 2016 ; Vol. 79, No. 3. pp. 419-427.
@article{6181a08503b346cf94ff360b6966a5ae,
title = "MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs",
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.",
author = "Albulym, {Obaid M.} and Kennerson, {Marina L.} and Harms, {Matthew B.} and Drew, {Alexander P.} and Siddell, {Anna H.} and Michaela Auer-Grumbach and Alan Pestronk and Anne Connolly and Baloh, {Robert H.} and Zuchner, {Stephan L} and Reddel, {Stephen W.} and Nicholson, {Garth A.}",
year = "2016",
month = "3",
day = "1",
doi = "10.1002/ana.24575",
language = "English (US)",
volume = "79",
pages = "419--427",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

TY - JOUR

T1 - MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs

AU - Albulym, Obaid M.

AU - Kennerson, Marina L.

AU - Harms, Matthew B.

AU - Drew, Alexander P.

AU - Siddell, Anna H.

AU - Auer-Grumbach, Michaela

AU - Pestronk, Alan

AU - Connolly, Anne

AU - Baloh, Robert H.

AU - Zuchner, Stephan L

AU - Reddel, Stephen W.

AU - Nicholson, Garth A.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84960431547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960431547&partnerID=8YFLogxK

U2 - 10.1002/ana.24575

DO - 10.1002/ana.24575

M3 - Article

VL - 79

SP - 419

EP - 427

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 3

ER -