TY - JOUR

T1 - Differential expression of the three independent CaM genes coding for an identical protein

T2 - Potential relevance of distinct mRNA stability by different codon usage

AU - Munk, Mads

AU - Villalobo, Eduardo

AU - Villalobo, Antonio

AU - Berchtold, Martin W.

N1 - Publisher Copyright: © 2022

PY - 2022

Y1 - 2022

N2 - The Ca2+-sensor protein calmodulin (CaM) is a major regulator of multiple cell functions. A unique and puzzling feature of human, and all so far investigated mammals, is the presence of three distinct CaM genes on different chromosomes, which code for identical proteins. How this case of apparent genetic redundancy evolved and why it could be to the advantage of the mammalian organisms is not well established. With a main focus on humans, this article aims to review existing literature addressing how the genes nonetheless differ in function. Clearly, the three CaM genes are differentially expressed in different tissues, during development, in response to different stimuli, and other factors including environmental conditions. As shown in hippocampal neurons, different mRNAs from the CAM genes may even localize differently within the same cell. Regulation of CaM gene expression is achieved by a variety of regulatory elements present in the three genes, including different promotor/insulator elements and 3′- and 5′-noncoding regions differing in length and sequence, as well as regulation by epigenetic factors and miRNAs. Here, we hypothesize that predicted differences in mRNA stability and translational efficiency due to divergent codon usage could play an additional regulatory role as the three genes differ markedly in their use of synonymous codons. CALM3, predicted to produce a relatively stable mRNA may be important where the transcription level is low or transiently absent, e.g. during spermatogenesis. In contrast, CALM2 with a predicted much shorter mRNA half-life, may provide better temporal control of CaM levels. Deciphering the underlying mechanisms responsible for all this complexity may help to understand why this unique multigenic arrangement may be an advantage for the optimal spatio-temporal expression of CaM in higher eukaryotes. Finally, we discuss the expression of the CaM genes in selected human pathologies, and how mutations in these genes are responsible for the appearance of serious congenital syndromes, mainly affecting the heart, and although less known, possibly also affecting the functionality of the central nervous system and other organs.

AB - The Ca2+-sensor protein calmodulin (CaM) is a major regulator of multiple cell functions. A unique and puzzling feature of human, and all so far investigated mammals, is the presence of three distinct CaM genes on different chromosomes, which code for identical proteins. How this case of apparent genetic redundancy evolved and why it could be to the advantage of the mammalian organisms is not well established. With a main focus on humans, this article aims to review existing literature addressing how the genes nonetheless differ in function. Clearly, the three CaM genes are differentially expressed in different tissues, during development, in response to different stimuli, and other factors including environmental conditions. As shown in hippocampal neurons, different mRNAs from the CAM genes may even localize differently within the same cell. Regulation of CaM gene expression is achieved by a variety of regulatory elements present in the three genes, including different promotor/insulator elements and 3′- and 5′-noncoding regions differing in length and sequence, as well as regulation by epigenetic factors and miRNAs. Here, we hypothesize that predicted differences in mRNA stability and translational efficiency due to divergent codon usage could play an additional regulatory role as the three genes differ markedly in their use of synonymous codons. CALM3, predicted to produce a relatively stable mRNA may be important where the transcription level is low or transiently absent, e.g. during spermatogenesis. In contrast, CALM2 with a predicted much shorter mRNA half-life, may provide better temporal control of CaM levels. Deciphering the underlying mechanisms responsible for all this complexity may help to understand why this unique multigenic arrangement may be an advantage for the optimal spatio-temporal expression of CaM in higher eukaryotes. Finally, we discuss the expression of the CaM genes in selected human pathologies, and how mutations in these genes are responsible for the appearance of serious congenital syndromes, mainly affecting the heart, and although less known, possibly also affecting the functionality of the central nervous system and other organs.

KW - Calmodulin genes

KW - Codon usage

KW - Epigenetic control

KW - miRNA control

KW - Mutation-mediated diseases

KW - Phylogeny

KW - Pseudogenes

U2 - 10.1016/j.ceca.2022.102656

DO - 10.1016/j.ceca.2022.102656

M3 - Review

C2 - 36252447

AN - SCOPUS:85139848481

VL - 107

JO - Cell Calcium

JF - Cell Calcium

SN - 0143-4160

M1 - 102656

ER -