κ-Casein-deficient mice fail to lactate

Abstract

Acquisition of milk production capabilities by an ancestor of mammals is at the root of mammalian evolution. Milk casein micelles are a primary source of amino acids and calcium phosphate to neonates. To understand the role of -casein in lactation, we have created and characterized a null mouse strain (Csnk ؊/؊ ) lacking this gene. The mutant -casein allele did not affect the expression of other milk proteins in Csnk ؊/؊ females. However, these females did not suckle their pups and failed to lactate because of destabilization of the micelles in the lumina of the mammary gland. Thus, -casein is essential for lactation and, consequently, for the successful completion of the process of reproduction in mammals. In view of the extreme structural conservation of the casein locus, as well as the phenotype of Csnk ؊/؊ females, we propose that the organization of a functional -casein gene would have been one of the critical events in the evolution of mammals. Further, -casein variants are known to affect the industrial properties of milk in dairy animals. Given the expenses and the time scale of such experiments in livestock species, it is desirable to model the intended genetic modifications in mice first. The mouse strain that we have created would be a useful model to study the effect of -casein variants on the properties of milk and͞or milk products.casein locus ͉ evolution ͉ lactation ͉ milk ͉ micelle M ilk production is an essential component of the reproductive strategy of mammals. The development of a zygote into an organism is accompanied by the preparation of milk synthesis potential by the mammary gland. Perinatal survival in mammals is solely dependent on the availability of milk from the mother. Caseins account for Ͼ80% of the total milk proteins (1). These proteins exist as micelles, consisting of three to four phosphoproteins (i.e., the calcium-sensitive caseins: ␣-, ␤-, ␥-, and ␦-casein in mice) and a calcium-insensitive phosphoglycoprotein, -casein (2). In addition to functioning as the primary source of amino acids, one of the key functions of micelles is to sequester large amounts of calcium phosphate from the maternal diet or bodily stores and make it readily available to the newborn. Calcium-sensitive casein genes seem to have evolved from a primitive casein gene through gene duplication and exon shuffling (3); however, it appears that -casein is not related structurally and evolutionarily to these genes. Instead, it appears to be related to ␥-fibrinogen (4, 5). Recently, it has also been speculated that both the calcium-sensitive and the calciuminsensitive casein gene belong to one gene family (6). The null mutation of the ␤-casein gene in mice (7) and that of ␣ S1 -casein in goats (8) do not show any significant effect on milk micelle formation and lactation. The lack of adverse effects on micelle formation in these mutants suggests functional redundancy amongst calcium-sensitive caseins. However, the absence of ␣ S1 -casein in goats does affect the rate of transport of caseins. The experimental ev...

Effect of κ-Casein Polymorphism on Milk Composition in the Orobica Goat

“…In addition, the genetic variation of κ-CN involving the mature protein could be associated with other polymorphisms in the noncoding sequences (promoter, introns), which might be causative mutations for the expression differences between some alleles, as has already been found for the 2 main bovine CSN3 alleles (reviewed by Martin et al, 2002). In all cases, quantitative differences at the κ-CN level must be closely considered because of the essential role of this CN in the process of reproduction in mammals; as recently demonstrated in mice, when a null mutation was introduced in κ-CN, it resulted in destabilization of the CN micelles and lactation failure (Shekar et al, 2006).…”

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

“…All milks contain an ortholog of κ-CN and, in the 6 examples where the composition of casein has been determined (Supplementary Table S1; http://dx.doi.org/10.3168/jds.2013-6831), the percentage of κ-CN in whole casein varies from less than 2% to more than 17% (Baranyi et al, 1995;Miranda et al, 2004;Boumahrou et al, 2009;Holt and Carver, 2012). So vital is this stabilization for the proper formation and functioning of casein micelles that mice made deficient in κ-CN fail to lactate (Shekar et al, 2006).…”

Frequency and association of polymorphisms in CSN3 gene with milk yield and composition in Saanen goats

“…It has also been suggested that the genetic variation in CSN3 implies that the mature protein could be associated with other polymorphisms in the non-coding sequences (promoter), which could be mutations that cause dierent expressions among some alleles, such as two main alleles in the CSN3 gene in bovine cattle (Martin et al 2002). Existing evidence has shown that when a null mutation was introduced in CSN3 and caused the destabilization of the casein micelles, there was a failure in the lactation process (Shekar et al 2006).…”