Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III

<p>Abstract</p> <p>Background</p> <p>Spinal muscular atrophy (SMA type I, II and III) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron gene (<it>SMN1</it>). <it>SMN2 </it>is a centromeric copy gene that has been characterized as a major modifier of SMA severity. SMA type I patients have one or two <it>SMN2 </it>copies while most SMA type II patients carry three <it>SMN2 </it>copies and SMA III patients have three or four <it>SMN2 </it>copies. The <it>SMN1 </it>gene produces a full-length transcript (FL-SMN) while <it>SMN2 </it>is only able to produce a small portion of the FL-SMN because of a splice mutation which results in the production of abnormal SMNΔ7 mRNA.</p> <p>Methods</p> <p>In this study we performed quantification of the <it>SMN2 </it>gene copy number in Russian patients affected by SMA type II and III (42 and 19 patients, respectively) by means of real-time PCR. Moreover, we present two families consisting of asymptomatic carriers of a homozygous absence of the <it>SMN1 </it>gene. We also developed a novel RT-qPCR-based assay to determine the FL-SMN/SMNΔ7 mRNA ratio as SMA biomarker.</p> <p>Results</p> <p>Comparison of the <it>SMN2 </it>copy number and clinical features revealed a significant correlation between mild clinical phenotype (SMA type III) and presence of four copies of the <it>SMN2 </it>gene. In both asymptomatic cases we found an increased number of <it>SMN2 </it>copies in the healthy carriers and a biallelic <it>SMN1 </it>absence. Furthermore, the novel assay revealed a difference between SMA patients and healthy controls.</p> <p>Conclusions</p> <p>We suggest that the <it>SMN2 </it>gene copy quantification in SMA patients could be used as a prognostic tool for discrimination between the SMA type II and SMA type III diagnoses, whereas the FL-SMN/SMNΔ7 mRNA ratio could be a useful biomarker for detecting changes during SMA pharmacotherapy.</p

UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration

Neurodegenerative diseases are a leading cause of disability and early death. A common feature of these conditions is disruption of protein homeostasis. Ubiquitin-like modifier activating enzyme 1 (UBA1), the E1 ubiquitin-activating enzyme, sits at the apex of the ubiquitin cascade and represents an important regulator of cellular protein homeostasis. Critical contributions of UBA1-dependent pathways to the regulation of homeostasis and degeneration in the nervous system are emerging, including specific disruption of UBA1 in spinal muscular atrophy (SMA) and Huntington's disease (HD). In this review we discuss recent findings that put UBA1 at the centre of cellular homeostasis and neurodegeneration, highlighting the potential for UBA1 to act as a promising therapeutic target for a range of neurodegenerative diseases

Detection of pemphigus autoantibodies by IIF and ELISA tests in patients with pemphigus vulgaris and foliaceus and in healthy relatives

BACKGROUND: Pemphigus is a life-threatening, autoimmune blistering disease, mediated by IgG autoantibodies. The aim of our study was to assess the usefulness of a new enzyme-linked immunosorbent assay (ELISA) in detecting circulating pemphigus autoantibodies, and to compare its sensitivity and specificity with the indirect immunofluorescence (IIF) test. We also established the frequency of occurrence of pemphigus autoantibodies in relatives of our patients. MATERIAL/METHODS: IIF and ELISA tests were performed in 24 patients with pemphigus vulgaris, 13 with pemphigus foliaceus, 56 healthy relatives, and 50 controls, selected according to sex and age. RESULTS: The obtained results revealed high specificity and sensitivity of ELISA, comparable to the IIF test, especially in patients who were in the active stage of the disease. We also showed that the profile of anti-Dsg 1 and/or anti-Dsg 3 autoantibodies is associated with the clinical variant of pemphigus. The frequency of occurrence of pemphigus autoantibodies in the relatives (24/55) performed by IIF was significantly higher (p<0.001) than in the controls (0/50). The same antibodies detected by ELISA (11/56) were less frequent. CONCLUSIONS: In clinically doubtful cases, in which autoantibodies titres by IIF are equal on both substrates (monkey and guinea pig esophagus), the assessment of the exact antibody profile (anti-Dsg 1 and/or anti-Dsg 3) is important to establish the subtype of pemphigus. The frequency of pemphigus antibody occurrence in healthy relatives seems not to be incidental, but further studies should be performed to explain this phenomenon