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Abstract
Background Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The approximately 50 known ALS-associated genes do not fully explain its heritability, which suggests the existence of yet unidentified causative genes. We report results of studies aimed at identification of the genetic cause of ALS in a pedigree (three patients) without mutations in the common ALS-causative genes.
Methods Clinical investigations included thorough neurological and non-neurological examinations and testings. Genetic analysis was performed by exome sequencing. Functional studies included identification of altered splicing by PCR and sequencing, and mutated proteins by western blot analysis. Apoptosis in the presence and absence of tunicamycin was assessed in transfected HEK293T cells using an Annexin-PE-7AAD kit in conjunction with flow cytometry.
Results Clinical features are described in detail. Disease progression in the patients of the pedigree was relatively slow and survival was relatively long. An RNF13 mutation was identified as the cause of the recessively inherited ALS in the pedigree. The gene is highly conserved, and its encoded protein (RING finger protein 13) can potentially affect various neurodegenerative-relevant functions, including protein homeostasis. The RNF13 splice site mutation caused expression of two mis-spliced forms of RNF13 mRNA and an aberrant RNF13 protein, and affected apoptosis.
Conclusion RNF13 was identified as a novel causative gene of recessively inherited ALS. The gene affects protein homeostasis, which is one of most important components of the pathology of neurodegeneration. The contribution of RNF13 to the aetiology of another neurodegenerative disease is discussed.
- motor neuron disease
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Footnotes
Contributors MK: recruitment of patients and family members, exome data analysis, mutation screening and segregation analysis in families by Sanger sequencing, cDNA synthesis and splicing analysis, vector design and cell transfections, western blot analysis, apoptosis assays, data analysis and contribution to writing of manuscript; SN and HS: patient identification and provision of clinical data; HM: data analysis; HT: mutation screening and segregation analysis in families by Sanger sequencing; EE: design and supervision of the research, and writing the manuscript. EE is the guarantor. All authors approved the final version of the manuscript.
Funding Funding was provided by the Iran National Science Foundation (grant no. 4005531).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Author note School of Biology, College of Science, University of Tehran, Tehran, Iran: Marzieh Khani, Hamidreza Moazzeni, Hanieh Taheri, Elahe Elahi. Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran: Shahriar Nafissi, Hosein Shamshiri.
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