Testing SIPA1L2 as a modifier of CMT1A using mouse models.
Document Type
Article
Publication Date
4-19-2024
Original Citation
Murray G,
Hines T,
Tadenev A,
Xu I,
Züchner S,
Burgess RW.
Testing SIPA1L2 as a modifier of CMT1A using mouse models. J Neuropathol Exp Neurol. 2024 Apr 19;83(5):318-330.
Keywords
JMG, Animals, Mice, Axons, Charcot-Marie-Tooth Disease, Genome-Wide Association Study, Muscle Weakness, Myelin Sheath
JAX Source
J Neuropathol Exp Neurol. 2024 Apr 19;83(5):318-330.
ISSN
1554-6578
PMID
38472136
DOI
https://doi.org/10.1093/jnen/nlae020
Grant
This work was supported by National Institutes of Health (grant numbers R21 NS116936, R24 NS098523, and R37 NS054154 to R.W.B.). Patient sequencing was supported by National Insti- tute of Neurological Disorders and Stroke U54 NS065712. The Scientific Services at The Jackson Laboratory are supported by National Cancer Institute (grant number CA34196). G.C.M. was supported by T32GM132006. T.J.H. was supported by funding from Uplifting Athletes’ Young Investigator Draft, the Charcot- Marie-Tooth Association, and NINDS K99 NS130151.
Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), leading to muscle weakness and loss of sensation in the hands and feet. A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.