Alternative titles; symbols
HGNC Approved Gene Symbol: NPTX1
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:80,466,834-80,476,607 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Spinocerebellar ataxia 50 | 620158 | Autosomal dominant | 3 |
The NPTX1 gene encodes a long neuronal pentraxin (NP1) that is synthesized in the endoplasmic reticulum (ER) and secreted, preferentially at excitatory synapses, where it has multiple regulatory functions (summary by Coutelier et al., 2022).
Neuronal pentraxin I (NP1) was identified in the rat as a binding protein for the snake venom toxin taipoxin (Schlimgen et al., 1995). Omeis et al. (1996) cloned the human NP1 homolog by screening a human cerebellar cDNA library with the rat Np1 gene as a probe. The gene, designated NPTX1, encodes a predicted 430-amino acid protein that is 95% identical to rat Np1. Northern blot analysis showed that the approximately 6-kb NPTX1 mRNA is expressed only in brain.
In adult mouse tissue, Coutelier et al. (2022) found expression of the Nptx1 gene in the brain and kidney. Nptx1 was detected in Purkinje cells in the cerebellum. These findings agreed with a human database that showed NPTX1 mRNA expression restricted to the central nervous system, particularly in the cerebellum. Overexpression of NPTX1 in COS7 cells showed that it localized to the ER.
Xu et al. (2003) found that rat Np1 was part of a pentraxin complex that included Narp (NPTX2). The proteins were covalently linked by disulfide bonds, and their relative ratio in the complex was dynamically dependent upon the activity history and developmental stage of the neuron. Narp was more effective than Np1 in assays of cell surface cluster formation, coclustering of AMPA-type glutamate receptors (see 138248), and excitatory synaptogenesis, but combined expression of Narp and Np1 resulted in supraadditive effects.
Omeis et al. (1996) used fluorescence in situ hybridization to map the NPTX1 gene to human chromosome 17q25.1-q25.2 and mouse chromosome 11e2-e1.3.
In affected members of 6 unrelated families with spinocerebellar ataxia-50 (SCA50; 620158), Coutelier et al. (2022) identified 2 different heterozygous missense mutations in the NPTX1 gene (G389R, 602367.0001 and E327G, 602367.0002). The mutations, which were found by exome sequencing or targeted sequencing, segregated with the disorder in families with available data. Neither were present in the gnomAD database. Five families carried the G389R mutation, although haplotype analysis excluded a founder effect. The mutant proteins localized to the ER when expressed in COS7 cells, but both caused abnormal and aggregated ER morphologies and hyperplasia of the ER with swollen cisternae, although there were some cytologic differences between the variants. These changes were associated with activation of the ER unfolded protein response (UPR), as evidenced by translocation of ATF6 (605537) to the nucleus and increased cell death. Additional studies indicated that the G389R variant likely resulted in a loss-of-function effect, whereas E327G disrupted NPTX1 secretion and multimerization in a dominant-negative manner. However, both mutations were predicted to result in ER stress, activation of the UPR, and a decrease in cellular viability.
In a man who had onset of SCA50 at age 47 years, Deppe et al. (2022) identified a de novo heterozygous missense mutation in the NPTX1 gene (R143L; 602367.0003). The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation could result in protein misfolding and possible aggregation of dysfunctional multimers.
In a 6-year-old girl, born of unrelated parents, who developed symptoms of SCA50 at 21 months of age, Schoggl et al. (2022) identified a de novo heterozygous missense mutation affecting the pentraxin domain of the NPTX1 gene (Q370R; 602367.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 9 affected members of a multigenerational family (AAD271) with autosomal dominant spinocerebellar ataxia-50 (SCA50; 620158), Coutelier et al. (2022) identified a heterozygous c.1165G-A transition (c.1165G-A, NM_002522.3) in the NPTX1 gene, resulting in a gly389-to-arg (G389R) substitution at a highly conserved residue in the pentraxin domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found once in the gnomAD database (1 of 251,148 alleles). The same heterozygous mutation was subsequently identified in affected members of 3 additional families with the disorder (families AAD347, LUEB01, and BER01). Another affected individual (family AAD938) carried the heterozygous NPTX1 mutation, but that patient also carried a heterozygous A754T missense variant in the SPTBN2 gene (604985) which may have contributed to the phenotype. Haplotype analysis excluded a founder effect for families AAD271 and AAD347. The mutant protein localized to the ER when expressed in COS7 cells, and caused abnormal and aggregated ER morphologies. These changes were associated with activation of the ER unfolded protein response (UPR) and ER stress, as evidenced by translocation of ATF6 (605537) to the nucleus and increased cell death. Expression of the G389R variant in COS7 cells showed that it did not interfere with NPTX1 secretion and did not modify NPTX1 interactions with other proteins. Molecular modeling predictions indicated that the variant would not change the stability of the pentameric complex in which NPTX1 is involved, but could alter interactions with other biomolecules. The authors postulated a loss-of-function effect of the mutation.
In a patient (family AAD498) with adult-onset spinocerebellar ataxia-50 (SCA50; 620158), Coutelier et al. (2022) identified a heterozygous c.980A-G transition (c.980A-G, NM_002522.3) in the NPTX1 gene, resulting in a glu327-to-gly (E327G) substitution at a highly conserved residue in the pentraxin domain. The mutation was found by exome sequencing. There were 3 additional affected family members by report, but genetic analysis of those patients was not performed, so segregation studies could not be done. Expression of the E327G mutation in COS7 cells totally abolished NPTX1 secretion with retention of the mutant protein inside the cell. Further studies showed that the E327G mutant impaired NPTX1 multimerization in a dominant-negative manner and induced abnormal contacts with several cytoskeletal proteins, suggesting alterations in protein conformation and decreased secretion of the mutant protein. The mutant protein localized to the ER when expressed in COS7 cells, but caused abnormal and aggregated ER morphologies. These changes were associated with activation of the ER unfolded protein response (UPR) and ER stress, as evidenced by translocation of ATF6 (605537) to the nucleus and increased cell death. Molecular modeling predictions were consistent with the hypothesis of loss of NPTX1 complex formation and a dominant-negative effect of the mutation.
In a man who had onset of spinocerebellar ataxia-50 (SCA50; 620158) at age 47 years, Deppe et al. (2022) identified a de novo heterozygous c.428G-T transversion (c.428G-T, ENST00000306773.4) in exon 1 of the NPTX1 gene, resulting in an arg143-to-leu (R143L) substitution at a highly conserved residue in the N-terminal domain. The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation could result in protein misfolding and possible aggregation of dysfunctional multimers.
In a 6-year-old girl, born of unrelated parents, who developed symptoms of spinocerebellar ataxia-50 (SCA50; 620158) at 21 months of age, Schoggl et al. (2022) identified a de novo heterozygous c.1109A-G transition (c.1109A-G, NM_002522.4) in exon 5 of the NPTX1 gene, resulting in a gln370-to-arg (Q370R) substitution at a highly conserved residue in the pentraxin domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Coutelier, M., Jacoupy, M., Janer, A., Renaud, F., Auger, N., Saripella, G.-V., Ancien, F., Pucci, F., Rooman, M., Gilis, D., Lariviere, R., Sgarioto, N., and 17 others. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia. Brain 145: 1519-1534, 2022. [PubMed: 34788392] [Full Text: https://doi.org/10.1093/brain/awab407]
Deppe, J., Deininger, N., Lingor, P., Haack, T. B., Haslinger, B., Deschauer, M. A novel NPTX1 de novo variant in a late-onset ataxia patient. Mov. Disord. 37: 1319-1321, 2022. [PubMed: 35285082] [Full Text: https://doi.org/10.1002/mds.28985]
Omeis, I. A., Hsu, Y.-C., Perin, M. S. Mouse and human neuronal pentraxin 1 (NPXT1): conservation, genomic structure, and chromosomal localization. Genomics 36: 543-545, 1996. [PubMed: 8884281] [Full Text: https://doi.org/10.1006/geno.1996.0503]
Schlimgen, A. K., Helms, J. A., Vogel, H., Perin, M. S. Neuronal pentraxin, a secreted protein with homology to acute phase proteins of the immune system. Neuron 14: 519-526, 1995. [PubMed: 7695898] [Full Text: https://doi.org/10.1016/0896-6273(95)90308-9]
Schoggl, J., Siegert, S., Boltshauser, E., Freilinger, M., Schmidt, W. M. A de novo missense NPTX1 variant in an individual with infantile-onset cerebellar ataxia. Mov. Disord. 37: 1774-1776, 2022. [PubMed: 35560436] [Full Text: https://doi.org/10.1002/mds.29054]
Xu, D., Hopf, C., Reddy, R., Cho, R. W., Guo, L., Lanahan, A., Petralia, R. S., Wenthold, R. J., O'Brien, R. J., Worley, P. Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity. Neuron 39: 513-528, 2003. [PubMed: 12895424] [Full Text: https://doi.org/10.1016/s0896-6273(03)00463-x]