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PLoS Genet. 2015 Aug 6;11(8):e1005388. doi: 10.1371/journal.pgen.1005388. eCollection 2015 Aug.

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

Author information

1
Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
2
Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
3
Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
4
Pediatric Endocrinology & Metabolism Unit, Soroka Medical Center, Beer Sheva, Israel.
5
Pediatric Neuromuscular Laboratory and Pediatric Neurology Unit Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
6
Pesticides and Mycotoxins Division, Aminolab, Weizmann Science Park, Ness Ziona, Israel.
7
Pediatric Neuromuscular Laboratory and Pediatric Neurology Unit Hadassah, Hebrew University Medical Center, Jerusalem, Israel; Institute of Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
8
Department of Pediatrics, Division of Medical Genetics and Hughes Medical Institute, University of Iowa, Iowa City, Iowa, United States of America.
9
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
10
Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, Beer Sheva, 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.

PMID:
26247364
PMCID:
PMC4527749
DOI:
10.1371/journal.pgen.1005388
[Indexed for MEDLINE]
Free PMC Article

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