What Genetics Has Told Us and How It Can Inform Future Experiments for Spinal Muscular Atrophy, a Perspective

• Published in: International journal of molecular sciences Vol. 22; no. 16; p. 8494
• Main Authors: Blatnik, 3rd, Anton J, McGovern, Vicki L, Burghes, Arthur H M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.08.2021; MDPI
• Subjects: Animals; Atrophy; Biochemistry; Clinical trials; Drug development; Gene therapy; Genetic engineering; Genetics; Genomes; Hereditary diseases; Humans; Motor Neurons - metabolism; Motor Neurons - pathology; Muscles; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Mutation; Neuromuscular diseases; Patients; Proteins; Ribonucleoproteins; Ribonucleoproteins (small nuclear); Signal Transduction; Skeletal muscle; SMA; SMN function; SMN missense mutants; SMN protein; Spinal muscular atrophy; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 1 Protein - metabolism; Survival of Motor Neuron 2 Protein - genetics; Survival of Motor Neuron 2 Protein - metabolism; SMN missense mutants; survival motor neuron; genetics; SMN function; SMA; motor neuron; biochemistry; spinal muscular atrophy; suppressor screen
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22168494

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential (SMN) protein, canonically responsible for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed at increasing SMN protein levels are efficacious in treating SMA. However, it remains unknown how deficiency of SMN results in motor neuron loss, resulting in many reported cellular functions of SMN and pathways affected in SMA. Herein is a perspective detailing what genetics and biochemistry have told us about SMA and SMN, from identifying the SMA determinant region of the genome, to the development of therapeutics. Furthermore, we will discuss how genetics and biochemistry have been used to understand SMN function and how we can determine which of these are critical to SMA moving forward.