Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

Abstract

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

Comprehensive In Silico Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy

“…This motor neuron degeneration leads to progressive muscle weakness and atrophy. This neurodegenerative disease affects approximately 1/6000 to 1/10,000 individuals and is the most common inherited cause of childhood mortality [ 26 ]. The carrier frequency for SMA is highly variable between populations, ranging between 1/25 to 1/50 [ 26 , 27 ].…”

“…This neurodegenerative disease affects approximately 1/6000 to 1/10,000 individuals and is the most common inherited cause of childhood mortality [ 26 ]. The carrier frequency for SMA is highly variable between populations, ranging between 1/25 to 1/50 [ 26 , 27 ]. Most cases of SMA result from a complete loss of Survival Motor Neuron 1 ( SMN1 ) but retention of the paralogous Survival Motor Neuron 2 ( SMN2 ) gene [ 26 , 27 , 28 ].…”

“…The carrier frequency for SMA is highly variable between populations, ranging between 1/25 to 1/50 [ 26 , 27 ]. Most cases of SMA result from a complete loss of Survival Motor Neuron 1 ( SMN1 ) but retention of the paralogous Survival Motor Neuron 2 ( SMN2 ) gene [ 26 , 27 , 28 ]. SMN1 and SMN2 are nearly identical except for 20 single nucleotide differences, with the C to T transition in exon 7 (c.840C > T) being the most functionally relevant difference [ 29 ].…”

Caracterización clínica y funcional de pacientes con atrofia muscular espinal en el centro-occidente colombiano

“…El gen SMN2 presenta una tendencia a un empalme génico alternativo (alternative splicing) durante la transcripción del ARNm que origina una proteína truncada, con solo el 10 % de la proteína SMN completa. Este gen puede ser un modificador de la enfermedad causada por una mutación en la copia telomérica (8). Se cree que los eventos de conversión de genes pueden involucrar los dos genes, lo que lleva a un número variable de copias de cada gen (7).…”

“…La gravedad de la atrofia muscular espinal clásica es muy variable (8), lo que resulta en características clínicas heterogéneas, las cuales pueden clasificarse en cinco fenotipos con base en la edad de inicio y la función motora máxima alcanzada. Debe considerarse como diagnóstico diferencial en la hipotonía congénita ya que, dependiendo de la alteración en el gen, se producen varios fenotipos.…”