Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Brennan KM, Bai Y, Shy ME (2015) Demyelinating CMT—what’s known, what’s new and what’s in store? Neurosci Lett 596:14–26

    Article  CAS  PubMed  Google Scholar 

  2. Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259–280

    Article  CAS  PubMed  Google Scholar 

  3. Timmerman V, Strickland A, Züchner S (2014) Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the human genome project success. Genes 5:13–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zimon M, Baets J, Almeida-Souza L, De Vriendt E, Nikodinovic J, Parman Y, Battaloglu E, Matur Z, Guergueltcheva V, Tournev I, Auer-Grumbach M, De Rijk P, Petersen BS, Muller T, Fransen E, Van Damme P, Loscher WN, Barisic N, Mitrovic Z, Previtali SC, Topaloglu H, Bernert G, Beleza-Meireles A, Todorovic S, Savic-Pavicevic D, Ishpekova B, Lechner S, Peeters K, Ooms T, Hahn AF, Zuchner S, Timmerman V, Van Dijck P, Rasic VM, Janecke AR, De Jonghe P, Jordanova A (2012) Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet 44:1080–1083

    Article  CAS  PubMed  Google Scholar 

  5. Cottenie E, Kochanski A, Jordanova A, Bansagi B, Zimon M, Horga A, Jaunmuktane Z, Saveri P, Rasic Vedrana M, Baets J, Bartsakoulia M, Ploski R, Teterycz P, Nikolic M, Quinlivan R, Laura M, Sweeney Mary G, Taroni F, Lunn Michael P, Moroni I, Gonzalez M, Hanna Michael G, Bettencourt C, Chabrol E, Franke A, von Au K, Schilhabel M, Kabzińska D, Hausmanowa-Petrusewicz I, Brandner S, Lim Siew C, Song H, Choi B-O, Horvath R, Chung K-W, Zuchner S, Pareyson D, Harms M, Reilly Mary M, Houlden H (2014) Truncating and missense mutations in IGHMBP2 cause Charcot-Marie-Tooth disease type 2. Am J Hum Genet 95:590–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ylikallio E, Woldegebriel R, Tumiati M, Isohanni P, Ryan MM, Stark Z, Walsh M, Sawyer SL, Bell KM, Oshlack A, Lockhart PJ, Shcherbii M, Estrada-Cuzcano A, Atkinson D, Hartley T, Tetreault M, Cuppen I, Ludo van der Pol W, Candayan A, Battaloglu E, Parman Y, van Gassen KLI, van den Boogaard M-JH, Boycott KM, Kauppi L, Jordanova A, Lönnqvist T, Tyynismaa H (2017) MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability. Brain 140(8):2093–2103

    Article  PubMed  Google Scholar 

  7. Lindner TH, Hoffmann K (2005) easyLINKAGE: a PERL script for easy and automated two-/multi-point linkage analyses. Bioinformatics 21:405–407

    Article  CAS  PubMed  Google Scholar 

  8. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  CAS  PubMed  Google Scholar 

  9. Cottingham RW, Idury RM, Schäffer AA (1993) Faster sequential genetic linkage computations. Am J Hum Genet 53:252–263

    PubMed  PubMed Central  Google Scholar 

  10. Matise TC, Chen F, Chen W, De La Vega FM, Hansen M, He C, Hyland FC, Kennedy GC, Kong X, Murray SS, Ziegle JS, Stewart WC, Buyske S (2007) A second-generation combined linkage physical map of the human genome. Genome Res 17:1783–1786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Drew AP, Zhu D, Kidambi A, Ly C, Tey S, Brewer MH, Ahmad-Annuar A, Nicholson GA, Kennerson ML (2015) Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. Mol Genet Genomic Med 3:143–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bahlo M, Bromhead CJ (2009) Generating linkage mapping files from Affymetrix SNP chip data. Bioinformatics 25:1961–1962

    Article  CAS  PubMed  Google Scholar 

  13. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blankenberg D, Von Kuster G, Coraor N, Ananda G, Lazarus R, Mangan M, Nekrutenko A, Taylor J (2010) Galaxy, a web-based genome analysis tool for experimentalists. Curr Protoc Mol Biol 0(19):Unit-19.1021

    Google Scholar 

  15. Goecks J, Nekrutenko A, Taylor J, Team TG (2010) Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences. Genome Biol 11:R86

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tey S, Ahmad-Annuar A, Drew AP, Shahrizaila N, Nicholson GA, Kennerson ML (2016) Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies. Clin Genet 90:127–133

    Article  CAS  PubMed  Google Scholar 

  17. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protocols 3:1101–1108

    Article  CAS  PubMed  Google Scholar 

  18. Shahrizaila N, Samulong S, Tey S, Suan LC, Meng LK, Goh KJ, Ahmad-Annuar A (2014) X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients. Muscle Nerve 49:198–201

    Article  CAS  PubMed  Google Scholar 

  19. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46(3):310–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Narasimhan VM, Hunt KA, Mason D, Baker CL, Karczewski KJ, Barnes MR, Barnett AH, Bates C, Bellary S, Bockett NA, Giorda K, Griffiths CJ, Hemingway H, Jia Z, Kelly MA, Khawaja HA, Lek M, McCarthy S, McEachan R, O’Donnell-Luria A, Paigen K, Parisinos CA, Sheridan E, Southgate L, Tee L, Thomas M, Xue Y, Schnall-Levin M, Petkov PM, Tyler-Smith C, Maher ER, Trembath RC, MacArthur DG, Wright J, Durbin R, van Heel DA (2016) Health and population effects of rare gene knockouts in adult humans with related parents. Science 352:474–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sano K, Miura S, Fujiwara T, Fujioka R, Yorita A, Noda K, Kida H, Azuma K, Kaieda S, Yamamoto K, Taniwaki T, Fukumaki Y, Hiroki S (2015) A novel missense mutation of RYR1 in familial idiopathis hyper CK-emia. J Neurol Sci 356(1–2):142–147

    Article  CAS  PubMed  Google Scholar 

  22. Nagata K, Takahashi M, Kiryu-Seo S, Hiroshi K, Saido TC (2017) Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders. Acta Neuropathol Commun 5:83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Komuro A, Masuda Y, Kobayashi K, Babbitt R, Gunel M, Flavell RA, Marchesi VT (2004) The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells. Proc Natl Acad Sci U S A 101:4053–4058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luzón-Toro B, Gui H, Ruiz-Ferrer M, Sze-Man Tang C, Fernández RM, Sham P-C, Torroglosa A, Kwong-Hang Tam P, Espino-Paisán L, Cherny SS, Bleda M, Enguix-Riego MV, Dopazo J, Antiñolo G, García-Barceló M-M, Borrego S (2015) Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease. Sci Rep 5:16473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI, Cupler E, Bohlega S, Faqeih E, Faden M, Alyounes B, Jaroudi D, Goljan E, Elbardisy H, Akilan A, Albar R, Aldhalaan H, Gulab S, Chedrawi A, Al Saud BK, Kurdi W, Makhseed N, Alqasim T, El Khashab HY, Al-Mousa H, Alhashem A, Kanaan I, Algoufi T, Alsaleem K, Basha TA, Al-Murshedi F, Khan S, Al-Kindy A, Alnemer M, Al-Hajjar S, Alyamani S, Aldhekri H, Al-Mehaidib A, Arnaout R, Dabbagh O, Shagrani M, Broering D, Tulbah M, Alqassmi A, Almugbel M, AlQuaiz M, Alsaman A, Al-Thihli K, Sulaiman RA, Al-Dekhail W, Alsaegh A, Bashiri FA, Qari A, Alhomadi S, Alkuraya H, Alsebayel M, Hamad MH, Szonyi L, Abaalkhail F, Al-Mayouf SM, Almojalli H, Alqadi KS, Elsiesy H, Shuaib TM, Seidahmed MZ, Abosoudah I, Akleh H, AlGhonaium A, Alkharfy TM, Al Mutairi F, Eyaid W, Alshanbary A, Sheikh FR, Alsohaibani FI, Alsonbul A, Al Tala S, Balkhy S, Bassiouni R, Alenizi AS, Hussein MH, Hassan S, Khalil M, Tabarki B, Alshahwan S, Oshi A, Sabr Y, Alsaadoun S, Salih MA, Mohamed S, Sultana H, Tamim A, El-Haj M, Alshahrani S, Bubshait DK, Alfadhel M, Faquih T, El-Kalioby M, Subhani S, Shah Z, Moghrabi N, Meyer BF, Alkuraya FS (2017) The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum Genet 136:921–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marg A, Haase H, Neumann T, Kouno M, Morano I (2010) AHNAK1 and AHNAK2 are costameric proteins: AHNAK1 affects transverse skeletal muscle fiber stiffness. Biochem Biophys Res Commun 401:143–148

    Article  CAS  PubMed  Google Scholar 

  27. Hohaus A, Person V, Behlke J, Schaper J, Morano I, Haase H (2002) The carboxyl-terminal region of ahnak provides a link between cardiac L-type Ca2+ channels and the actin-based cytoskeleton. FASEB J 16:1205–1216

    Article  CAS  PubMed  Google Scholar 

  28. Huang Y, Laval SH, van Remoortere A, Baudier J, Benaud C, Anderson LVB, Straub V, Deelder A, Frants RR, den Dunnen JT, Bushby K, van der Maarel SM (2007) AHNAK, a novel component of the dysferlin protein complex, redistributes to the cytoplasm with dysferlin during skeletal muscle regeneration. FASEB J 21:732–742

    Article  CAS  PubMed  Google Scholar 

  29. Davies TA, Loos B, Engelbrecht AM (2014 Dec) AHNAK: the giant jack of all trades. Cell Signal 26(12):2683–2693

    Article  CAS  Google Scholar 

  30. Han H, Kursula P (2014) Periaxin and AHNAK nucleoprotein 2 form intertwined homodimers through domain swapping. J Biol Chem 289:14121–14131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gillespie CS, Sherman DL, Blair GE, Brophy PJ (1994) Periaxin, a novel protein of myelinating Schwann cells with a possible role in axonal ensheathment. Neuron 12:497–508

    Article  CAS  PubMed  Google Scholar 

  32. Guilbot A, Williams A, Ravise N, Verny C, Brice A, Sherman DL, Brophy PJ, LeGuern E, Delague V, Bareil C, Megarbane A, Claustres M (2001) A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum Mol Genet 10:415–421

    Article  CAS  PubMed  Google Scholar 

  33. Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, Lupski JR (2001) Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet 68:325–333

    Article  CAS  PubMed  Google Scholar 

  34. Kirov A, Kacer D, Conley BA, Vary CP, Prudovsky I (2015) AHNAK2 participates in the stress-induced nonclassical FGF1 secretion pathway. J Cell Biochem 116:1522–1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hossain WA, Morest DK (2000) Fibroblast growth factors (FGF-1, FGF-2) promote migration and neurite growth of mouse cochlear ganglion cells in vitro: immunohistochemistry and antibody perturbation. J Neurosci Res 62:40–55

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Marina L. Kennerson and Azlina Ahmad-Annuar contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Shelisa Tey, Sarimah Samulong & Azlina Ahmad-Annuar

  2. Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Nortina Shahrizaila & Khean-Jin Goh

  3. Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia

    Alexander P. Drew, Garth A. Nicholson & Marina L. Kennerson

  4. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    Alexander P. Drew, Garth A. Nicholson & Marina L. Kennerson

  5. Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey

    Esra Battaloglu

  6. Molecular Neurogenomics Group, VIB-U Antwerp Center for Molecular Neurology, University of Antwerp, 2610, Antwerpen, Belgium

    Derek Atkinson & Albena Jordanova

  7. Department of Neurology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey

    Yesim Parman

  8. Department of Biological Sciences, Kongju National University, Gongju, South Korea

    Ki Wha Chung

  9. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Byung-Ok Choi

  10. Department of Neurology, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, 11221, Taiwan

    Yi-Chung Li

  11. Department of Orthopedics and Trauma Surgery, Medical University of Vienna, 1090, Vienna, Austria

    Michaela Auer-Grumbach

  12. Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia

    Garth A. Nicholson & Marina L. Kennerson

Authors
  1. Shelisa Tey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nortina Shahrizaila
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander P. Drew
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarimah Samulong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Khean-Jin Goh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Esra Battaloglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Derek Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yesim Parman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Albena Jordanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ki Wha Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Byung-Ok Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yi-Chung Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michaela Auer-Grumbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Garth A. Nicholson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marina L. Kennerson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Azlina Ahmad-Annuar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Marina L. Kennerson or Azlina Ahmad-Annuar.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 354 kb)

ESM 2

(PDF 179 kb)

ESM 3

(PDF 819 kb)

ESM 4

(PDF 814 kb)

ESM 5

(DOCX 47 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tey, S., Shahrizaila, N., Drew, A.P. et al. Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family. Neurogenetics 20, 117–127 (2019). https://doi.org/10.1007/s10048-019-00576-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-019-00576-3

Keywords

Search

Navigation