MYO1H is a novel candidate gene for autosomal dominant pure hereditary spastic paraplegia

Ece Selçuk, Koray Kırımtay, Benan Temizci, Şeyma Akarsu, Elif Everest, Mehmet Barış Baslo, Meltem Demirkıran, Zuhal Yapıcı, Arzu Karabay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we aimed to determine the genetic basis of a Turkish family related to hereditary spastic paraplegia (HSP) by exome sequencing. HSP is a progressive neurodegenerative disorder and displays genetic and clinical heterogeneity. The major symptoms are muscle weakness and spasticity, especially in the lower extremities. We studied seven affected and seven unaffected family members, as well as a clinically undetermined member, to identify the disease-causing gene. Exome sequencing was performed for four affected and two unaffected individuals. The variants were firstly filtered for HSP-associated genes, and we found a common variant in the ZFYVE27 gene, which has been previously implied for association with HSP. Due to the incompletely penetrant segregation pattern of the ZFYVE27 variant, revealed by Sanger sequencing, with the disease in this family, filtering was re-performed according to the mode of inheritance and allelic frequencies. The resulting 14 rare variants were further evaluated in terms of their cellular functions, and three candidate variants in ATAD3C, VPS16, and MYO1H genes were selected as possible causative variants, which were analyzed for their familial segregation. ATAD3C and VPS16 variants were eliminated due to incomplete penetrance. Eventually, the MYO1H variant NM_001101421.3:c.2972_2974del (p.Glu992del, rs372231088) was found as the possible disease-causing deletion for HSP in this family. This is the first study reporting the possible role of a MYO1H variant in HSP pathogenesis. Further studies on the cellular roles of Myo1h protein are needed to validate the causality of MYO1H gene at the onset of HSP.

Original languageEnglish
Pages (from-to)1141-1150
Number of pages10
JournalMolecular Genetics and Genomics
Volume297
Issue number4
DOIs
Publication statusPublished - Jul 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Funding

This work was supported by Istanbul Technical University BAP 1239-39586 to AK for ES.

FundersFunder number
Istanbul Teknik ÜniversitesiBAP 1239-39586

    Keywords

    • Candidate gene
    • Hereditary spastic paraplegia
    • MYO1H
    • Novel gene
    • WES

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