Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function

Authors

Sitvanit Haziza, Ben-Gurion University of the Negev, Israel
Roberta Magnani, University of KentuckyFollow
Dima Lan, Ben-Gurion University of the Negev, Israel
Omer Keinan, Ben-Gurion University of the Negev, Israel
Ann Saada, Hebrew University, Israel
Eli Hershkovitz, Soroka Medical Center, Israel
Nurit Yanay, Hebrew University, Israel
Yoram Cohen, Aminolab, Israel
Yoram Nevo, Hebrew University, Israel
Robert L. Houtz, University of KentuckyFollow
Val C. Sheffield, University of Iowa
Hava Golan, Ben-Gurion University of the Negev, Israel
Ruti Parvari, Ben-Gurion University of the Negev, Israel

Abstract

Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene.

Document Type

Article

Publication Date

8-6-2015

Notes/Citation Information

Published in PLOS Genetics, v. 11, no. 8, article e1005388, p. 1-22.

© 2015 Haziza et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pgen.1005388

Funding Information

The study was partially funded by grant number 787/05 of Israel Science Foundation to RP. The fund provided for the creation of the mouse model and its initial characterization. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Haziza, Sitvanit; Magnani, Roberta; Lan, Dima; Keinan, Omer; Saada, Ann; Hershkovitz, Eli; Yanay, Nurit; Cohen, Yoram; Nevo, Yoram; Houtz, Robert L.; Sheffield, Val C.; Golan, Hava; and Parvari, Ruti, "Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function" (2015). Horticulture Faculty Publications. 23.
https://uknowledge.uky.edu/horticulture_facpub/23