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Erschienen in: neurogenetics 3/2019

22.04.2019 | Original Article

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

verfasst von: 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. Kennerson, Azlina Ahmad-Annuar

Erschienen in: Neurogenetics | Ausgabe 3/2019

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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.
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Metadaten
Titel
Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family
verfasst von
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. Kennerson
Azlina Ahmad-Annuar
Publikationsdatum
22.04.2019
Verlag
Springer Berlin Heidelberg
Erschienen in
Neurogenetics / Ausgabe 3/2019
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI
https://doi.org/10.1007/s10048-019-00576-3

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