MINPP1, multiple inositol-polyphosphate phosphatase 1, is an enzyme crucial for inositol polyphosphate metabolism. It hydrolyzes inositol phosphates in the endoplasmic reticulum lumen and is involved in maintaining the balance of inositol polyphosphate levels, which are vital metabolic and secondary messengers in diverse cellular functions like calcium homeostasis, cell survival, and apoptosis [3,5]. It may also play a role in pathways related to brain development, cell growth, and stress-induced apoptosis [1,2,4,5]. Genetic models, such as gene-knockout mouse models, have been valuable in studying its functions.

Minpp1-deficient mice were viable and fertile without obvious defects, yet biochemical analyses showed that levels of inositol 1,3,4,5,6-pentakisphosphate (InsP(5)) and inositol hexakisphosphate (Ins(6)) were 30-45% higher in Minpp1-deficient embryonic fibroblasts compared to wild-type cells, indicating that ER-based Minpp1 is significant in maintaining steady-state levels of these polyphosphates [4]. In humans, loss-of-function mutations in MINPP1 cause an early-onset neurodegenerative syndrome, Pontocerebellar Hypoplasia, characterized by inefficient neuronal differentiation, increased cell death, and an intracellular imbalance of inositol polyphosphate metabolism with an accumulation of inositol hexakisphosphate (IP6) [1]. Homozygous variants in MINPP1 have been found in children with Pontocerebellar hypoplasia, with different variants predicted to affect protein structure and function [2].

In conclusion, MINPP1 is essential for regulating inositol polyphosphate metabolism, which is crucial for normal cell physiology. The study of Minpp1-deficient mouse models has provided insights into its role in maintaining inositol polyphosphate levels. In humans, mutations in MINPP1 are associated with Pontocerebellar Hypoplasia, highlighting its importance in human brain development and homeostasis [1,2,4].

References:

1. Ucuncu, Ekin, Rajamani, Karthyayani, Wilson, Miranda S C, Saiardi, Adolfo, Cantagrel, Vincent. 2020. MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia. In Nature communications, 11, 6087. doi:10.1038/s41467-020-19919-y. https://pubmed.ncbi.nlm.nih.gov/33257696/

2. Appelhof, Bart, Wagner, Matias, Hoefele, Julia, Wieczorek, Dagmar, Jamra, Rami Abou. 2020. Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1. In European journal of human genetics : EJHG, 29, 411-421. doi:10.1038/s41431-020-00749-x. https://pubmed.ncbi.nlm.nih.gov/33168985/

3. Zubair, Mohd, Hamzah, Rabab, Griffin, Robert, Ali, Nawab. 2022. Identification and functional characterization of multiple inositol polyphosphate phosphatase1 (Minpp1) isoform-2 in exosomes with potential to modulate tumor microenvironment. In PloS one, 17, e0264451. doi:10.1371/journal.pone.0264451. https://pubmed.ncbi.nlm.nih.gov/35235602/

4. Chi, H, Yang, X, Kingsley, P D, Shears, S B, Reynolds, P R. . Targeted deletion of Minpp1 provides new insight into the activity of multiple inositol polyphosphate phosphatase in vivo. In Molecular and cellular biology, 20, 6496-507. doi:. https://pubmed.ncbi.nlm.nih.gov/10938126/

5. Kilaparty, Surya P, Agarwal, Rakhee, Singh, Pooja, Kannan, Krishnaswamy, Ali, Nawab. 2016. Endoplasmic reticulum stress-induced apoptosis accompanies enhanced expression of multiple inositol polyphosphate phosphatase 1 (Minpp1): a possible role for Minpp1 in cellular stress response. In Cell stress & chaperones, 21, 593-608. doi:10.1007/s12192-016-0684-6. https://pubmed.ncbi.nlm.nih.gov/27038811/