ABSTRACT
Heterozygous pathogenic variants in the STIP1 homologous and U-box containing protein 1 (STUB1) gene have been identified as causes of autosomal dominant inherited spinocerebellar ataxia type 48 (SCA48). SCA48 is characterized by an ataxic movement disorder that is often, but not always, accompanied by a cognitive affective syndrome. We report a severe early onset dementia syndrome that mimics frontotemporal dementia and is caused by the intronic splice donor variant c.524+1G>A in STUB1. Impaired splicing was demonstrated by RNA analysis and in minigene assays of mutated and wild-type constructs of STUB1. The most striking consequence of this splicing impairment was retention of intron 3 in STUB1, which led to an in-frame insertion of 63 amino acids (aa) (p.Arg175_Glu176ins63) into the highly conserved coiled-coil domain of its encoded protein, C-terminus of HSP70-interacting protein (CHIP). To a lesser extent, activation of two cryptic splice sites in intron 3 was observed. The almost exclusively used one, c.524+86, was not predicted by in silico programs. Variant c.524+86 caused a frameshift (p.Arg175fs*93) that resulted in a truncated protein and presumably impairs the C-terminal U-box of CHIP, which normally functions as an E3 ubiquitin ligase. The cryptic splice site c.524+99 was rarely used and led to an in-frame insertion of 33 aa (p.Arg175_Glu176ins33) that resulted in disruption of the coiled-coil domain, as has been previously postulated for complete intron 3 retention. We additionally detected repeat expansions in the range of reduced penetrance in the TATA box-binding protein (TBP) gene by excluding other genes associated with dementia syndromes. The repeat expansion was heterozygous in one patient but compound heterozygous in the more severely affected patient. Therefore, we concluded that the observed severe dementia syndrome has a digenic background, making STUB1 and TBP important candidate genes responsible for early onset dementia syndromes.
ABSTRACT
Stimulation of thermogenic pathways appears to be a promising approach to find new ways of tackling metabolic diseases like obesity and diabetes mellitus type 2. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 (PDE 5) inhibitors have recently been postulated, suggesting that modulators of endogenous cGMP signaling have the therapeutic potential to treat metabolic disorders. However, most studies have been performed in vitro or in animals that were not glucose intolerant. We, thus, aimed to test the metabolic effects of the PDE 5 inhibitor sildenafil by treating diet-induced obese (DIO) mice orally for 8 days. Surprisingly, our results revealed no changes in body temperature, brown adipose tissue (BAT) thermogenesis and gene expression in BAT and inguinal white adipose tissue (iWAT), thus excluding a thermogenic or 'browning' effect of sildenafil in preexisting obesity. In contrast, sildenafil-treated DIO mice displayed changes in liver metabolism and glucose homeostasis resulting in impaired glucose tolerance (P < 0.05), demonstrating for the first time an unfavorable metabolic effect of increased hepatic cGMP signaling in obesity. As sildenafil is commonly prescribed to treat pulmonary arterial hypertension and erectile dysfunction in diabetic and/or obese patients, follow up studies are urgently required to re-evaluate the drug safety.
