Design of functional small interfering RNAs targeting amyotrophic lateral sclerosis-associated mutant alleles / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>RNA interference (RNAi) is a potential cure for amyotrophic lateral sclerosis (ALS) caused by dominant, gain-of-function superoxide dismutase 1 (SOD1) mutations. The success of such therapy relies on the functional small interfering RNAs (siRNAs) that can effectively deliver RNAi. This study aimed to design the functional siRNAs targeting ALS-associated mutant alleles.</p><p><b>METHODS</b>A modified dual luciferase system containing human SOD1 mRNA target was established to quantify siRNA efficacy. Coupled with validated siRNAs identified in the literature, we analyzed the rationale of siRNA design and subsequently developed an asymmetry rule-based strategy for designing siRNA. We then further tested the effectiveness of this design strategy in converting a naturally symmetric siRNA into functional siRNAs with favorable asymmetry for gene silencing of SOD1 alleles.</p><p><b>RESULTS</b>The efficacies of siRNAs could vary tremendously by one base-pair position change. Functional siRNAs could target the whole span of SOD1 mRNA coding sequence as well as non-coding region. While there is no distinguishable pattern of the distribution of nucleobases in these validated siRNAs, the high percent of GC count at the last two positions of siRNAs (P18 and P19) indicated a strong effect of asymmetry rule. Introducing a mismatch at position 1 of the 5' of antisense strand of siRNA successfully converted the inactive siRNA into functional siRNAs that silence SOD1 with desired efficacy.</p><p><b>CONCLUSIONS</b>Asymmetry rule-based strategy that incorporates a mismatch into siRNA most consistently enhances RNAi efficacy and guarantees producing functional siRNAs that successfully silence ALS-associated SOD1 mutant alleles regardless target positions. This strategy could also be useful to design siRNAs for silencing other disease-associated dominant, gain-of-function mutant genes.</p>

Migraine as a sex-conditioned inherited disorder: evidences from China and the world / 神经科学通报·英文版

Migraine is a complex and heterogeneous disorder. Although several genetic models has been proposed including autosomal-dominant/autosomal recessive, sex-linked, sex-limited, mitochondrial, and multi-gene, none of these models can well-explain the transmission of the disease. We hypothesied that migraine is a sex-conditioned inherited disorder (autosomal dominant in females and autosomal recessive in males). This hypothesis is supported by the evidence such as the locations of genes associated with familial hemiplegic migraine, possibly "typical" migraine as well (dominantly on chromosome 19p, 1q, and 2q), male:female ratio of prevalence (1:2-1:4), the mostly youth-onset, the provocation by the contraceptives, the induction by menstruation, and the self-limitation after menopause. Female sex-hormones appear to be the key contributor to a higher prevalence of migraine in female. Socio-environmental factors may also play an important role.