title: Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function.
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.
authors.affiliation: Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Sitvanit
authors.initials: S
authors.lastname: Haziza
authors.affiliation: Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Roberta
authors.initials: R
authors.lastname: Magnani
authors.affiliation: Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Dima
authors.initials: D
authors.lastname: Lan
authors.affiliation: Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Omer
authors.initials: O
authors.lastname: Keinan
authors.affiliation: Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Pediatric Endocrinology & Metabolism Unit, Soroka Medical Center, Beer Sheva, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Hershkovitz
authors.affiliation: Pediatric Neuromuscular Laboratory and Pediatric Neurology Unit Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Yanay
authors.affiliation: Pesticides and Mycotoxins Division, Aminolab, Weizmann Science Park, Ness Ziona, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Houtz
authors.affiliation: Department of Pediatrics, Division of Medical Genetics and Hughes Medical Institute, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Hava
authors.initials: H
authors.lastname: Golan
authors.affiliation: 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.
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000503:physiopathology; D002872:Chromosome Deletion; D056228:Feedback, Sensory; D005260:Female; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D011499:Protein Processing, Post-Translational
chemical_list: D008780:Methyltransferases; C026647:calmodulin methyltransferase