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neurogenetics

, Volume 20, Issue 3, pp 117–127 | Cite as

Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

  • Shelisa Tey
  • Nortina Shahrizaila
  • Alexander P. Drew
  • Sarimah Samulong
  • Khean-Jin Goh
  • Esra Battaloglu
  • Derek Atkinson
  • Yesim Parman
  • Albena Jordanova
  • Ki Wha Chung
  • Byung-Ok Choi
  • Yi-Chung Li
  • Michaela Auer-Grumbach
  • Garth A. Nicholson
  • Marina L. KennersonEmail author
  • Azlina Ahmad-AnnuarEmail author
Original Article
  • 191 Downloads

Abstract

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11–q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.

Keywords

Inherited neuropathy AHNAK2 Autosomal recessive CMT 

Notes

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Shelisa Tey
    • 1
  • Nortina Shahrizaila
    • 2
  • Alexander P. Drew
    • 3
    • 4
  • Sarimah Samulong
    • 1
  • Khean-Jin Goh
    • 2
  • Esra Battaloglu
    • 5
  • Derek Atkinson
    • 6
  • Yesim Parman
    • 7
  • Albena Jordanova
    • 6
  • Ki Wha Chung
    • 8
  • Byung-Ok Choi
    • 9
  • Yi-Chung Li
    • 10
  • Michaela Auer-Grumbach
    • 11
  • Garth A. Nicholson
    • 3
    • 4
    • 12
  • Marina L. Kennerson
    • 3
    • 4
    • 12
    Email author
  • Azlina Ahmad-Annuar
    • 1
    Email author
  1. 1.Department of Biomedical Science, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  2. 2.Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  3. 3.Northcott Neuroscience Laboratory, ANZAC Research InstituteUniversity of SydneyConcordAustralia
  4. 4.Sydney Medical SchoolUniversity of SydneySydneyAustralia
  5. 5.Department of Molecular Biology and GeneticsBogazici UniversityIstanbulTurkey
  6. 6.Molecular Neurogenomics Group, VIB-U Antwerp Center for Molecular NeurologyUniversity of AntwerpAntwerpenBelgium
  7. 7.Department of Neurology, Istanbul School of MedicineIstanbul UniversityIstanbulTurkey
  8. 8.Department of Biological SciencesKongju National UniversityGongjuSouth Korea
  9. 9.Department of Neurology, Samsung Medical CenterSeoulSouth Korea
  10. 10.Department of Neurology, Taipei Veterans General HospitalNational Yang-Ming University School of MedicineTaipeiTaiwan
  11. 11.Department of Orthopedics and Trauma SurgeryMedical University of ViennaViennaAustria
  12. 12.Molecular Medicine LaboratoryConcord HospitalConcordAustralia

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