TY - JOUR
T1 - A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice
AU - Workman, Eileen
AU - Saieva, Luciano
AU - Carrel, Tessa L.
AU - Crawford, Thomas O.
AU - Liu, Don
AU - Lutz, Cathleen
AU - Beattie, Christine E.
AU - Pellizzoni, Livio
AU - Burghes, Arthur H.M.
N1 - Funding Information:
This work was supported by NIH grant NS038650, the SMA Angels and the Madison Fund to A.H.M.B. Transgenic creation was supplemented by grant P30NS04578. Zebrafish work was supported by NIH grant NS050414 to C.E.B. L.P. is supported by grants from the SMA Foundation and the Motor Neuron Center of Columbia University. C.L. is supported by the SMA Foundation.
PY - 2009
Y1 - 2009
N2 - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease. Loss of the survival motor neuron (SMN1) gene, in the presence of the SMN2 gene causes SMA. SMN functions in snRNP assembly in all cell types, however, it is unclear how this function results in specifically motor neuron cell death. Lack of endogenous mouse SMN (Smn) in mice results in embryonic lethality. Introduction of two copies of human SMN2 results in a mouse with severe SMA, while one copy of SMN2 is insufficient to overcome embryonic lethality. We show that SMN(A111G), an allele capable of snRNP assembly, can rescue mice that lack Smn and contain either one or two copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) cannot rescue Smn-/- mice without SMN2 suggesting that both SMN(A111G) and SMN from SMN2 undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) has substantial snRNP assembly activity. Also, the SMN(A2G) and SMN(A111G) alleles in vivo did not complement each other leading to the possibility that these mutations could affect the same function.
AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease. Loss of the survival motor neuron (SMN1) gene, in the presence of the SMN2 gene causes SMA. SMN functions in snRNP assembly in all cell types, however, it is unclear how this function results in specifically motor neuron cell death. Lack of endogenous mouse SMN (Smn) in mice results in embryonic lethality. Introduction of two copies of human SMN2 results in a mouse with severe SMA, while one copy of SMN2 is insufficient to overcome embryonic lethality. We show that SMN(A111G), an allele capable of snRNP assembly, can rescue mice that lack Smn and contain either one or two copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) cannot rescue Smn-/- mice without SMN2 suggesting that both SMN(A111G) and SMN from SMN2 undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) has substantial snRNP assembly activity. Also, the SMN(A2G) and SMN(A111G) alleles in vivo did not complement each other leading to the possibility that these mutations could affect the same function.
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U2 - 10.1093/hmg/ddp157
DO - 10.1093/hmg/ddp157
M3 - Article
C2 - 19329542
AN - SCOPUS:66149118977
SN - 0964-6906
VL - 18
SP - 2215
EP - 2229
JO - Human molecular genetics
JF - Human molecular genetics
IS - 12
ER -