The many faces of SMN : deciphering the function critical to spinal muscular atrophy pathogenesis

10.2217/FNL.10.57 © 2010 Rashmi Kothary Spinal muscular atrophy (SMA) is the most com‐ mon genetic disease resulting in infant death, affecting approximately 1 in 6000–10,000 births [1,2]. This autosomal recessive disease is characterized by a loss of a‐motor neurons in the spinal cord and brain stem, accompanied by atrophy of the limbs and trunk musculature, which eventually lead to paralysis and in severe cases, death [1]. Spinal muscular atrophy is a heterogeneous disease and its clinical manifestations are classi‐ fied based on age of onset and severity of symp‐ toms (Table 1). Type 0 SMA has a prenatal onset and is typified by reduced fetal movements in utero and early neonatal death [3,4]. Types I, II and III all have an infant/childhood onset of disease; however, type I SMA (also known as Werdnig–Hoffman disease) is the most severe form and afflicts patients with symptoms before 6 months of age. These patients are never able to sit up and usually die before 2 years of age due to respiratory distress. Type II and III SMA (also known as Kugelberg–Welander disease) are milder forms where patients exhibit symp‐ toms between 6 months and 17 years of age. Type II children are generally able to stand and sit but not walk, while type III adults have the ability to walk if aided [5,6]. Finally, individu‐ als with type IV SMA, an adult‐onset form of the disease, develop symptoms over the age of 30 years [2]. At the genetic level, SMA is the result of homo‐ zygous mutations or deletions of the survival motor neuron (SMN)1 gene located on human chromosome 5q13 [7]. SMN has been highly conserved throughout evolution with almost all eukaryotic organisms studied to date having one single copy of the gene. In humans, however, there is a duplication of the SMN gene resulting in two near‐identical copies known as SMN1 and SMN2 [7,8]. The critical difference between SMN1 and SMN2 is a C to T substitution in the SMN2 gene at position 6 of exon 7 [9]. SMN1 expresses a full‐length protein while SMN2 pre‐ dominantly expresses a truncated and unstable isoform of the protein, termed D7SMN, char‐ acterized by a deletion of exon 7 [7]. Recently, it was shown that the instability of the D7SMN protein is due to a degradation signal (degron) created by the exclusion of exon 7 in the SMN2 transcript [10]. While deletions or mutations in SMN1 but not SMN2 cause SMA, the latter can modulate the severity of the disease through its copy number owing to its production of a small amount of full‐length protein [7]. Indeed, patients affected by the milder forms of SMA generally have a higher copy number of the SMN2 gene [11]. Thus, SMA is considered to be a dosage‐sensitive disorder. The full‐length SMN protein (38 kDa) is expressed in all cells of the developing embryo, albeit with a developmental and tissue‐specific The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis