Alternative titles; symbols
HGNC Approved Gene Symbol: NIPA1
SNOMEDCT: 732949006;
Cytogenetic location: 15q11.2 Genomic coordinates (GRCh38): 15:22,786,225-22,829,789 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q11.2 | Spastic paraplegia 6, autosomal dominant | 600363 | Autosomal dominant | 3 |
NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor (Rainier et al., 2003).
By genomic sequence analysis to identify novel genes adjacent to the imprinted domain in the Prader-Willi syndrome (PWS; 176270)/Angelman (AS; 105830) syndrome deletion region of chromosome 15, Chai et al. (2003) identified NIPA1. The NIPA1 transcript contains 2 polyadenylation signals, and the deduced 329-amino acid protein contains 9 transmembrane domains. Within the coding region of the 5-prime end of the transcript, a (GCG)n repeat encodes a polyalanine stretch. Chai et al. (2003) also cloned mouse Nipa1, which encodes a deduced protein of 323 amino acids that is 98% identical to human NIPA1. The N-terminal polyalanine sequence in mouse is encoded by a (GCG)3-GCT-(GCG)3 sequence, and the transcript has 2 polyadenylation signals. Northern blot analysis detected transcripts of 1.9 and 7.5 kb in all mouse tissues examined, with enrichment in brain.
Chai et al. (2003) determined that the NIPA1 gene contains 5 exons and spans 38.8 kb. The mouse Nipa1 gene contains 5 exons and spans 41.1 kb. A CpG island spans the 5-prime untranslated region and part of exon 1, where it encodes an N-terminal polyalanine stretch. Alternative splicing in human gives rise to exons 3 and 3b.
By genomic sequence analysis, Chai et al. (2003) mapped the NIPA1 gene to chromosome 15q11.2, within a region deleted in some cases of PWS and AS. NIPA1 lies within a gene cluster distal to breakpoint hotspot 1 (BP1) and proximal to BP2. The order of genes within this cluster is cen-NIPA1-NIPA2 (608146)-CYFIP1 (606322)-GCP5 (608147)-BP2-tel. Chai et al. (2003) mapped the mouse Nipa1 gene to a region of chromosome 7C that contains the same gene cluster and shows homology of synteny to human chromosome 15q11-q13.
Tsang et al. (2009) showed that mammalian NIPA1 is an inhibitor of BMP signaling. NIPA1 physically interacted with the type II BMP receptor (BMPR2; 600799), and this interaction did not require the cytoplasmic tail of BMPR2. The mechanism by which NIPA1 inhibited BMP signaling involved downregulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 altered the trafficking of BMPR2 and were less efficient at promoting BMPR2 degradation than wildtype NIPA1. In addition, 2 other endosomal HSP proteins, spastin (SPAST; 604277) and spartin (SPG20; 607111), inhibited BMP signaling. Since BMP signaling is important for distal axonal function, Tsang et al. (2009) proposed that dysregulation of BMP signaling could be a unifying pathologic component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.
Chai et al. (2003) found that the polyalanine stretch of NIPA1 showed polymorphism within 135 chromosomes of European and Asian origin, with the number of repeats ranging from 6 to 10. The most frequent alleles, (GCG)8 and (GCG)7, had allele frequencies of 0.78 and 0.2, respectively.
By replication-timing studies, Chai et al. (2003) determined that replication of the mouse genomic region spanning Nipa1-Nipa2-Cyfip1 showed a pattern of asynchrony, but the asynchrony was not due to parent-of-origin influences. PCR of mouse brain cDNA from transgenic PWS and AS mouse models indicated that the Nipa1, Nipa2, Cyfip1, and Gcp5 genes are nonimprinted. RT-PCR detected expression of the human NIPA1, NIPA2, CYFIP1, and GCP5 genes in lymphocytes from a normal individual and from PWS and AS imprinting mutation patients. CYFIP1 was expressed from both the maternal and paternal chromosome 15 in somatic cell hybrids, further indicating that these 4 genes are nonimprinted.
Spastic Paraplegia 6
Rainier et al. (2003) analyzed a large kindred in which autosomal dominant hereditary spastic paraplegia mapped to the SPG6 locus on 15q11-q13 (600363) and found no evidence of genetic imprinting (Fink et al., 1995). Therefore, they analyzed as SPG6 candidates the 4 unique, nonimprinted, and highly evolutionarily conserved genes mapped proximal to the imprinted domain and within the pericentromeric region of 15q (Chai et al., 2003). In 28 affected subjects with SPG6, Rainier et al. (2003) identified a mutation in the NIPA1 gene (608145.0001).
In the large family with many members affected with autosomal dominant hereditary spastic paraplegia (SPG6; 600363) reported by Fink et al. (1995), Rainier et al. (2003) demonstrated a 159C-G transversion in NIPA1 cDNA, resulting in a thr45-to-arg (T45R) substitution. The same mutation was found in an unrelated kindred with autosomal dominant hereditary spastic paraplegia that was too small for meaningful linkage analysis.
In affected members of 2 unrelated Chinese families with spastic paraplegia-6 (APG6; 600363), Chen et al. (2005) identified 2 mutations involving the same nucleotide in exon 3 of the NIPA1 gene, 316G-C and 316G-A (608145.0002), both of which resulted in a gly106-to-arg (G106R) substitution. Structural predictions suggested that G106 is located in the third transmembrane domain of the protein and that the mutant G106R disrupts this structure, causing the intramembrane loop to descend into the cytoplasm. The results suggested that nucleotide 316 of the NIPA1 gene may be a mutation hotspot.
For discussion of the c.316G-A transition in the NIPA1 gene, resulting in a gly106-to-arg (R106R) substitution, that was found in compound heterozygous state in affected members of 2 unrelated Chinese families with spastic paraplegia-6 (SPG6; 600363) by Chen et al. (2005), see 608145.0002.
In affected members of a large British family with SPG6 (600363), Reed et al. (2005) identified a heterozygous 341G-A transition in exon 3 of the NIPA1 gene, resulting in a gly106-to-arg (G106R) substitution in a highly conserved central portion of the third transmembrane segment of the protein. The mutation was not identified in unaffected family members or in 224 control chromosomes.
Chai, J.-H., Locke, D. P., Greally, J. M., Knoll, J. H. M., Ohta, T., Dunai, J., Yavor, A., Eichler, E. E., Nicholls, R. D. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am. J. Hum. Genet. 73: 898-925, 2003. [PubMed: 14508708] [Full Text: https://doi.org/10.1086/378816]
Chen, S., Song, C., Guo, H., Xu, P., Huang, W., Zhou, Y., Sun, J., Li, C.-X., Du, Y., Li, X., Liu, Z., Geng, D., Maxwell, P. H., Zhang, C., Wang, Y. Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. Hum. Mutat. 25: 135-141, 2005. [PubMed: 15643603] [Full Text: https://doi.org/10.1002/humu.20126]
Fink, J. K., Sharp, G. B., Lange, B. M., Wu, C. B., Haley, T., Otterud, B., Peacock, M., Leppert, M. Autosomal dominant, familial spastic paraplegia, type I: clinical and genetic analysis of a large North American family. Neurology 45: 325-331, 1995. [PubMed: 7854534] [Full Text: https://doi.org/10.1212/wnl.45.2.325]
Fink, J. K., Wu, C. B., Jones, S. M., Sharp, G. B., Lange, B. M., Lesicki, A., Reinglass, T., Varvil, T., Otterud, B., Leppert, M. Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am. J. Hum. Genet. 56: 188-192, 1995. [PubMed: 7825577]
Rainier, S., Chai, J.-H., Tokarz, D., Nicholls, R. D., Fink, J. K. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am. J. Hum. Genet. 73: 967-971, 2003. [PubMed: 14508710] [Full Text: https://doi.org/10.1086/378817]
Reed, J. A., Wilkinson, P. A., Patel, H., Simpson, M. A., Chatonnet, A., Robay, D., Patton, M. A., Crosby, A. H., Warner, T. T. A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia. Neurogenetics 6: 79-84, 2005. [PubMed: 15711826] [Full Text: https://doi.org/10.1007/s10048-004-0209-9]
Tsang, H. T. H., Edwards, T. L., Wang, X., Connell, J. W., Davies, R. J., Durrington, H. J., O'Kane, C. J., Luzio, J. P., Reid, E. The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling. Hum. Molec. Genet. 18: 3805-3821, 2009. [PubMed: 19620182] [Full Text: https://doi.org/10.1093/hmg/ddp324]