STUB1polyadenylation signal variant AACAAA does not affect polyadenylation but decreasesSTUB1translation causing SCAR16

Abstract

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.

Extending the Phenotypic Spectrum Associated with STUB1 Mutations: A Case of Dystonia

“…All described patients had ataxia with 86.2% having dysarthria and 62% having cognitive impairment (Table ) . Dystonia was reported in 3/29 (10.3%) patients with SCAR16 in the literature (including our patient) . The prevalence of dystonia is equal to the prevalence of chorea/choreoathetosis and ophthalmoplegia in this condition .…”

“…Dystonia was reported in 3/29 (10.3%) patients with SCAR16 in the literature (including our patient) . The prevalence of dystonia is equal to the prevalence of chorea/choreoathetosis and ophthalmoplegia in this condition . The genetic testing for mutations in STUB1 gene should be therefore kept in mind while assessing patients with ataxia and dystonia and the reason is twofold.…”

“…Our patient is one of the oldest to develop SCAR16 (ATX‐ STUB1 ) described in the literature where age at onset ranged from a few months to age 57 (there were 3 patients older than our patient [aged 49, 54, and 57], whereas all others were younger than age 33). All described patients had ataxia with 86.2% having dysarthria and 62% having cognitive impairment (Table ) . Dystonia was reported in 3/29 (10.3%) patients with SCAR16 in the literature (including our patient) .…”

“…This entity was first described in 2014 by Shi and colleagues in 4 siblings from China, all of whom had dysarthria . To date, there have been 15 families (with 29 members) reported with SCAR16 (ATX‐ STUB1 ; detailed phenotypic data including our patient are presented in Table ) . A total of 20 pathogenic variants in the STUB1 gene causing SCAR16 (ATX‐ STUB1 ) have been described, including truncation, missense, and splice site donor mutation .…”

“…2,3 To date, there have been 15 families (with 29 members) reported with SCAR16 (ATX-STUB1; detailed phenotypic data including our patient are presented in Table 1). [2][3][4][5][6][7][8][24][25][26] A total of 20 pathogenic variants in the STUB1 gene causing SCAR16 (ATX-STUB1) have been described, including truncation, missense, and splice site donor mutation. [2][3][4][5][6][7][8] Dystonia in SCAR16 (ATX-STUB1) has been described in 1 report of 2 brothers (of 3 affected family members by SCAR16) by Kawarai and colleagues.…”