Intragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice.

Vicki L McGovern, Kaitlyn M Kray, W David Arnold, Sandra I Duque, Chitra C Iyer, Aurélie Massoni-Laporte, Eileen Workman, Aalapi Patel, Daniel J Battle, Arthur H M Burghes

Human molecular genetics 2020 Nov 01

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Spinal muscular atrophy is caused by reduced levels of SMN resulting from the loss of SMN1 and reliance on SMN2 for the production of SMN. Loss of SMN entirely is embryonic lethal in mammals. There are several SMN missense mutations found in humans. These alleles do not show partial function in the absence of wild-type SMN and cannot rescue a null Smn allele in mice. However, these human SMN missense allele transgenes can rescue a null Smn allele when SMN2 is present. We find that the N- and C-terminal regions constitute two independent domains of SMN that can be separated genetically and undergo intragenic complementation. These SMN protein heteromers restore snRNP assembly of Sm proteins onto snRNA and completely rescue both survival of Smn null mice and motor neuron electrophysiology demonstrating that the essential functional unit of SMN is the oligomer. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Citation

Vicki L McGovern, Kaitlyn M Kray, W David Arnold, Sandra I Duque, Chitra C Iyer, Aurélie Massoni-Laporte, Eileen Workman, Aalapi Patel, Daniel J Battle, Arthur H M Burghes. Intragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice. Human molecular genetics. 2020 Nov 01;29(21):3493-3503