NIPA1 Membrane Protein Introduction

Introduction of NIPA1

The NIPA1 gene consists of five exons and encodes a 329 amino acid NIPA1 protein containing nine transmembrane domains and is thought to play a role in cellular magnesium metabolism. NIPA1 typically encodes a Mg²⁺ transporter and the loss of function of NIPA1 establishes the basis of SP phenotype. Subcellular localization with immunofluorescence revealed that endogenous NIPA1 protein is associated with cell surface in early endosomes and various neuronal and epithelial cells. High concentrations of magnesium ions lead to a decrease of NIPA1 on the cell surface, while low concentrations of magnesium ions lead to accumulation in early endosomes and recruitment of plasma membranes. The 5' end of NIPA1 contains a polyalanine repeat of 12-13 alanine residues. Some disease phenotypes are caused by polyalanine expansion in other genes, such as ocular dystrophies and Ondine syndrome.

Function of NIPA1 Membrane Protein

The NIPA1 mutation in humans and animals causes hereditary spastic paraplegia (HSP) type 6, a neurodegenerative disorder characterized by a motor neuron phenotype. The NIPA1 allele with a long polyalanine repeat increases the risk of Amyotrophic lateral sclerosis and is associated with a younger age when the disease is independently onset. Therefore, from the genetic and biological view, NIPA1 may be a reasonable candidate gene for the treatment of Amyotrophic lateral sclerosis. In vitro studies have shown that NIPA1 is an inhibitor of bone morphogenetic protein (BMP) signaling. NIPA1 interacts with the type II BMP receptor (BMPRII) and promotes its degradation by endocytosis and lysosomal degradation. The regulation of BMP signaling by NIPA1 in Drosophila is critical for synaptic growth and regulation of axon microtubules. Therefore, loss of function of the NIPA1 mutation or NIPA1 polyalanine amplification may be important causes of synaptic and axonal developmental defects.

Fig.1 The figure shows the predicted secondary structure of mouse NIPA1. Two mouse mutation sites T39R and G100R corresponding to the respective human T45R and G106R mutations are shown. (Goytain, 2007)

Application of NIPA1 Membrane Protein in Literature

1. Svenstrup K., et al. NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. European Journal of Neurology. 2011, 18(9): 1197-9. PubMed ID: 21599812
   
   

   This article finds that NIPA1 mutations are found in patients with complex HSP and epilepsy may be more common in spastic paraplegia type 6 than in other forms of hereditary spastic paraplegia because NIPA1 is closely related to heredity.

2. Goytain A., et al. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg²⁺ transporter. Journal of Biological Chemistry. 2007, 282(11): 8060-8. PubMed ID: 17166836
   
   

   This article suggests that NIPA1 typically encodes a Mg²⁺ transporter and the loss of function of NIPA1 (SPG6) due to abnormal transport of the mutant protein establishes the basis for the HSP phenotype.

3. Arkadir D., et al. Pure hereditary spastic paraplegia due to a de-novo mutation in the NIPA1 gene. European journal of neurology. 2014, 21(1): e2. PubMed ID: 25133278
   
   

   This article reports a family with a pure form of HSP due to a de novo transition mutation in the NIPA1 gene.

4. Blauw H.M., et al. NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis. Human Molecular Genetics. 2012, 21(11): 2497-502. PubMed ID: 22378146
   
   

   This article reveals that repeated amplification of NIPA1 polyalanine is a common risk factor for amyotrophic lateral sclerosis and disease regulation.

5. Du J., et al. Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1. Clinical Neurology & Neurosurgery. 2011, 113(6): 480-2. PubMed ID: 21419568
   
   

   This article reports the world's first complex case of SPG6 through the presence of peripheral neuropathy, which extends the phenotype of SPG6.

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Reference

1. Goytain A, et al. (2007). NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg²⁺ transporter. Journal of Biological Chemistry. 282(11): 8060-8.

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