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Kappa-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 kappa-casein in lactation, we have created and characterized a null mouse strain (Csnk-/-) lacking this gene. The mutant kappa-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, kappa-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 kappa-casein gene would have been one of the critical events in the evolution of mammals. Further, kappa-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 kappa-casein variants on the properties of milk and/or milk products.

SUBMITTER: Shekar PC

PROVIDER: S-EPMC1472419 | biostudies-other | 2006 May

REPOSITORIES: biostudies-other

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kappa-casein-deficient mice fail to lactate.

Shekar P Chandra PC Goel Sandeep S Rani S Deepa Selvi SD Sarathi D Partha DP Alex Jomini Liza JL Singh Shashi S Kumar Satish S

Proceedings of the National Academy of Sciences of the United States of America 20060512 21

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 kappa-casein in lactation, we have created and characterized a null mouse strain (Csnk-/-) lacking this gene. The mutant kappa-casein allele did not affect the expression of other milk proteins in Csnk-/- females. However, these females did not suckle their pups and failed ...[more]

PMID: 16698927

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Project description:Milk alpha-, beta- and kappa-casein proteins assemble into casein micelles in breast epithelial cells. The glycomacropeptide (GMP) tails of kappa-casein that extend from the surface of the micelle are key to assembly and aggregation. Aggregation is triggered by stomach pepsin cleavage of GMP from para-kappa-casein (PKC). While one casein micelle model emphasizes the importance of hydrophobic interactions, another focuses on polar residues. We performed an evolutionary analysis of kappa-casein primary sequence and predicted features that potentially impact on protein interactions. We noted more rapid change in the earlier period (166 to 60 Ma). Pepsin and plasmin cleavage sites were avoided in the GMP, which may partly explain its amino acid composition. Short tandem repeats have led to modest expansions of PKC, and to large GMP expansions, suggesting the GMP is less length constrained. Amino acid compositional constraints were assessed across species. Polarity and hydrophobicity properties were insufficient to explain differences between PKC and GMP. Among polar residues, threonine dominates the GMP, compared to serine, probably reflecting its preference for O-glycosylation over phosphorylation. Glutamine, enriched in the bovine PQ-rich region, is not positionally conserved in other species. Among hydrophobic residues, isoleucine is clearly preferred over leucine in the GMP, and patches of hydrophobicity are not markedly positionally conserved. PKC tyrosine and charged residues showed stronger conservation of position, suggesting a role for pi-interactions, seen in other structurally dynamic protein membraneless assemblies. Independent acquisitions of cysteines are consistent with a trend of increasing stabilization of multimers by covalent disulphide bonds, over evolutionary time. In conclusion, kappa-casein compositional and positional constraints appear to be influenced by modification preferences, protease evasion and protein-protein interactions.

Project description:BackgroundDuchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs).MethodsUsing a metabolomics-based approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most chronically depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit using two complementary small molecule strategies: provision of a biosynthetic precursor, nicotinamide riboside, or specific inhibition of the NAD-degrading ADP-ribosyl cyclase, CD38.ResultsAdministering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, with a pronounced impact on intermediates of the pentose phosphate pathway, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy sustainably increased the bulk tissue NAD pool, lessened muscle damage markers, nor improved maximal hindlimb strength following repeated rounds of eccentric challenge and recovery.ConclusionsIn the absence of dystrophin, eccentric injury contributes to chronic intramuscular NAD depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These molecular consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside. However, we found no evidence that either small molecule strategy is sufficient to restore muscle contractile function or confer protection from eccentric injury, undermining the modulation of NAD metabolism as a therapeutic approach for DMD.

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Kappa-casein-deficient mice fail to lactate.

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kappa-casein-deficient mice fail to lactate.

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