No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland

Abstract

Linkage analysis in Brazilian families with amyotrophic lateral sclerosis (ALS) revealed that a missense mutation p.Pro56Ser in a conserved gene VAMP-associated protein type B and C (VAPB) cosegregates with disease. Blood samples were studied from 973 Swedish, 126 Portuguese and 19 Icelandic ALS patients, and from 644 control subjects. We identified five VAPB mutations, two of which are novel, in 14 Swedish ALS patients and in nine control individuals from Sweden and Portugal. The 14 patients with VAPB mutations all carried a diagnosis of sporadic ALS. Mutations were also found in healthy adult relatives. The p.Asp130Glu VAPB mutation was also found in two patients from an Icelandic ALS family, but the mutation did not cosegregate with disease. All patients were instead found to be heterozygous for a p.Gly93Ser SOD1 mutation. There were no clinical differences between them, suggesting that the p.Asp130Glu VAPB mutation is unrelated to the disease process.

In conclusion, the VAPB mutations were as frequent in control individuals as in patients. This observation, in combination with the finding of several healthy relatives carrying the VAPB mutations and no ancestors with ALS disease, suggests that it is unlikely that these VAPB mutations are pathogenic.

Key words::

• ALS
• risk factor
• VAPB
• SOD1
• oligomutant

Acknowledgements

We are indebted to the patients and their families for participation in this study. We are also grateful to the clinicians who provided patient material, in particular Olof Häggblom and Rune Johansson. We also thank Ann-Charloth Nilsson, Helena Alstermark and Sabine Björk for technical assistance.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This study was generously supported by grants from the Swedish Brain Power Consortium, the Bertil Hållsten Foundation, the Swedish Brain Research Foundation, the Swedish Research Council, Umeå University, the Ulla-Carin Lindquist Foundation, and the Swedish Association for the Neurologically Disabled (NHR). The sources of funding had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.