نمونه متن انگلیسی مقاله
Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.
Spinal muscular atrophy (SMA) is a genetic disease caused by homozygous deletion, truncation, mutation or gene conversion of survival motor neuron 1 (SMN1) [1–4]. SMN2, a nearly identical copy of SMN1, fails to compensate for the loss of SMN1 owing to a cytosine to thymidine mutation at the 6th position (C6U in the transcript) of exon 7. C6U triggers predominant skipping of SMN2 exon 7 due to disruption of an exonic splicing enhancer and/or creation of an exonic splicing silencer [5–7]. The resultant decrease in full-length transcript reduces functional SMN, since the translated product (SMNΔ7) of the truncated transcript is unstable and rapidly degraded [8–10]. The copy number of SMN2 modulates the severity of SMA: the more SMN2 copies the less severe the disease due to higher levels of the full-length transcript and functional SMN [11–13]. Thus, treatment strategies to halt the disease progression and ameliorate the symptoms have primarily focused on means to increase full-length SMN2 transcript and functional SMN. The multifunctional SMN has been implicated in snRNP biogenesis [14–17], transcription [18,19], splicing , translation , signal transduction , stress granule formation  and intra-cellular trafficking . With respect to neuron-specific functions, SMN facilitates interaction of mRNA binding proteins and participates in mRNA transport across the axonal processes of motor neurons [25–27]. SMN modulates axon outgrowth and cytoskeletal dynamics through β actin localization [28–30]. Preventing SMN transport across axons causes growth cone collapse . SMN also plays an important role in postnatal muscle nerve terminal maturation and reduction in SMN levels is predicted to negatively affect neurotransmission . Defects in snRNP biogenesis correlate with the severity of SMA, although only a subset of snRNPs is preferentially affected . Supporting these arguments, motor neurons of Smn deficient Drosophila show decreased expression of a subset of certain genes containing the U12 type introns .