New insights into NPP1 function: lessons from clinical and animal studies
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Published on: June 11, 2017
N C W Mackenzie1, C Huesa, F Rutsch
1The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush, Roslin, Midlothian, EH25 9RG, Scotland, UK.
Abstract:
The recent elucidation of rare human genetic disorders resulting from mutations in ectonucleotide pyrophosphotase/phosphodiesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), has highlighted the vital importance of this molecule in human health and disease. Generalised arterial calcification in infants (GACI), a frequently lethal disease, has been reported in recessive inactivating mutations in ENPP1. Recent findings have also linked hypophosphataemia to a lack of NPP1 function. A number of human genetic studies have indicated that NPP1 is a vital regulator that influences a wide range of tissues through various signalling pathways and when disrupted can lead to significant pathology. The function of Enpp1 has been widely studied in rodent models, where both the mutant tiptoe walking (ttw/ttw) mouse and genetically engineered Enpp1(-/-) mice show significant alterations in skeletal and soft tissue mineralisation, calcium/phosphate balance and glucose homeostasis. These models therefore provide important tools with which to study the potential mechanisms underpinning the human diseases associated with altered NPP1. This review will focus on the recent advances in our current knowledge of the actions of NPP1 in relation to bone disease, cardiovascular pathologies and diabetes. A fuller understanding of the mechanisms through which NPP1 exerts its pathological effects may stimulate the development of novel therapeutic strategies for patients at risk from the devastating clinical outcomes associated with disrupted NPP1 function.
Insights
Mutations in ectonucleotide pyrophosphotase/phosphodiesterase 1 (ENPP1) cause severe genetic disorders. Understanding ENPP1
Area of Science:
- Biochemistry and Molecular Biology
- Genetics
- Physiology
Background:
- Mutations in ectonucleotide pyrophosphotase/phosphodiesterase 1 (ENPP1), also known as PC-1, are linked to human genetic disorders.
- ENPP1 plays a critical role in human health, with inactivating mutations causing diseases like generalized arterial calcification in infants (GACI) and hypophosphatemia.
Purpose of the Study:
- To review recent advances in understanding ENPP1's role in bone disease, cardiovascular pathologies, and diabetes.
- To explore the mechanisms underlying ENPP1's pathological effects.
- To stimulate the development of novel therapeutic strategies for ENPP1-related disorders.
Main Methods:
- Review of recent scientific literature on ENPP1 function and associated human diseases.
- Analysis of findings from rodent models (ttw/ttw and Enpp1(-/-) mice) that exhibit altered mineralization, calcium/phosphate balance, and glucose homeostasis.
- Focus on genetic studies and their implications for understanding ENPP1's regulatory functions.
Main Results:
- ENPP1 is a vital regulator influencing multiple tissues via various signaling pathways.
- Disrupted ENPP1 function leads to significant pathology, including skeletal and soft tissue mineralization defects, impaired calcium/phosphate balance, and glucose homeostasis issues.
- Rodent models provide valuable tools for studying mechanisms of human diseases linked to altered ENPP1.
Conclusions:
- A comprehensive understanding of ENPP1's mechanisms is crucial for developing effective therapies.
- Targeting ENPP1 pathways may offer novel treatment options for devastating clinical outcomes associated with its dysfunction.
- Further research into ENPP1's diverse roles is warranted to address associated pathologies.