Recurrent de novo c.316G>A mutation in NIPA1 hotspot

Mutations in the NIPA1 cause autosomal dominant form of hereditary spastic paraplegia. Allelic heterogeneity of known NIPA1 mutations is quite limited and the most common mutation is c.316G>A resulting in p.G106R protein change. Here we report the first direct evidence of de novo c.316G>A mutation in the same hotspot of the gene in two unrelated patients who had otherwise a prototypical NIPA1-associated phenotype with a severe form of uncomplicated spastic paraplegia. De novo nature of these mutations was confirmed by sequencing both sets of clinically unaffected parents and confirmation of paternity. We also discuss likely molecular mechanisms accounting for recurrent mutations in this segment of the gene. Apparently sporadic patients without a positive family history of hereditary spastic paraplegia need to be also evaluated for possible disease-causing mutations in genes that are inherited in an autosomal dominant fashion.