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GNE missense mutation in recessive familial amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease eventually leading to death from respiratory failure. Recessive inheritance is very rare. Here, we describe the clinical findings in a consanguineous family with five men afflicted with recessive ALS and the identification of the homozygous mutation responsible for the disorder. The onset of the disease ranged from 12 to 35 years of age, with variable disease progressions. We performed clinical investigations including metabolic and paraneoplastic screening, cranial and cervical imaging, and electrophysiology. We mapped the disease gene to 9p21.1-p12 with a LOD score of 5.2 via linkage mapping using genotype data for single-nucleotide polymorphism markers and performed exome sequence analysis to identify the disease-causing gene variant. We also Sanger sequenced all coding sequences of SIGMAR1, a gene reported as responsible for juvenile ALS in a family. We did not find any mutation in SIGMAR1. Instead, we identified a novel homozygous missense mutation p.(His705Arg) in GNE which was predicted as damaging by online tools. GNE has been associated with inclusion body myopathy and is expressed in many tissues. We propose that the GNE mutation underlies the pathology in the family.

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Acknowledgements

We thank the family members for their cooperation, Dr. Aslıhan Tolun for supervising the genetic studies and her contribution to writing the manuscript, and TÜBITAK Advanced Genomics and Bioinformatics Group (IGBAM) for sharing with us the Turkish Exome Database.

Funding

This work was supported by the Boğaziçi University Research Fund grant number 5708 and the Scientific and Technological Research Council of Turkey grant number 110T252 (to AT).

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Author notes

  1. Çiğdem Köroğlu and Rezzak Yılmaz equally contributed to the article.

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Boğaziçi University, 34342, Istanbul, Turkey

    Çiğdem Köroğlu

  2. Department of Neurology, School of Medicine, Ankara University, 06230, Ankara, Turkey

    Rezzak Yılmaz, Mine Hayriye Sorgun & Özden Şener

  3. Department of Histology, Istanbul Medical School, Istanbul University, 34390, Istanbul, Turkey

    Seyhun Solakoğlu

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  1. Çiğdem Köroğlu
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Corresponding author

Correspondence to Çiğdem Köroğlu.

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The study protocol was approved by the Boğaziçi University Institutional Review Board for Research with Human Participants. Informed consent was obtained from all the subjects according to the regulations of the board.

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Electronic supplementary material

Supplementary Figure 1

Simplified pedigree used for the initial whole-genome multipoint linkage analysis on Allegro. Because of the limitations in the program, unaffected siblings were not included and consanguinity between 407 and 408 was disregarded. (GIF 11 kb)

High resolution image (TIFF 2971 kb)

Supplementary Figure 2

Multipoint LOD scores for chromosomes that yielded positive scores. A, initial calculations for autosomes and pseudoautosomal regions using Allegro. B, detailed calculations using SimWalk at loci that yielded LOD scores > 3 in the initial analysis. (PDF 4733 kb)

Supplementary Figure 3

Chromatograms showing the candidate variant GNE c.2114A>G (p.His705Arg). (GIF 39 kb)

High resolution image (TIFF 5173 kb)

Supplementary Table 1

The list of all exonic and splicing variants detected at the disease locus 9p21.1-p12. False calls as indicated by IGV inspection, as well as variants with allele frequencies > 0.05, were filtered out. Novel, homozygous variant c.A2114G (p.His705Arg) in GNE was selected as the candidate mutation. (XLS 58 kb)

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Köroğlu, Ç., Yılmaz, R., Sorgun, M.H. et al. GNE missense mutation in recessive familial amyotrophic lateral sclerosis. Neurogenetics 18, 237–243 (2017). https://doi.org/10.1007/s10048-017-0527-3

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  • DOI: https://doi.org/10.1007/s10048-017-0527-3

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