STUB1 polyadenylation signal variant AACAAA does not affect polyadenylation but decreases STUB1 translation causing SCAR16

We present three siblings afflicted with a disease characterized by cerebellar ataxia, cerebellar atrophy, pyramidal tract damage with increased lower limb tendon reflexes, and onset of 31 to 57 years, which is not typical for a known disease. In a region of shared homozygosity in patients, exome sequencing revealed novel homozygous c.*240T > C variant in the 3′UTR of STUB1, the gene responsible for autosomal recessive spinocerebellar ataxia 16 (SCAR16). In other genes, such an alteration of the evolutionarily highly conserved polyadenylation signal from AATAAA to AACAAA is known to highly impair polyadenylation. In contrast, RNA sequencing and quantification revealed that neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered. We propose that this change underlies the extremely low amounts of the encoded protein in patient leukocytes. In three siblings with cerebellar ataxia linkage mapping and exome sequencing identified homozygous c.*240T > C variant in the 3′UTR of STUB1. Alteration of thepolyadenylation signal from AATAAA to AACAAA is expected to highly impair polyadenylation. In contrast, neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered, indicating that most probably this change underlies the extremely low amounts of the encoded protein in patient leukocytes.