Open AccessIntragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice
Author(s) -
Vicki L. McGovern,
Kaitlyn M. Kray,
W. David Arnold,
Sandra Duqué,
Chitra C. Iyer,
Aurélie MassoniLaporte,
Eileen Workman,
Arsheya Patel,
Daniel J. Battle,
Arthur Burghes
Publication year - 2020
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddaa235
Subject(s) - biology , smn1 , null allele , missense mutation , complementation , spinal muscular atrophy , genetics , allele , microbiology and biotechnology , mutant , gene , mutation
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.