Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINI1
SNOMEDCT: 702421006;
Cytogenetic location: 3q26.1 Genomic coordinates (GRCh38): 3:167,735,721-167,825,569 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.1 | Encephalopathy, familial, with neuroserpin inclusion bodies | 604218 | Autosomal dominant | 3 |
The PI12 gene encodes neuroserpin, a serine protease inhibitor that is a member of the serpin superfamily. Alpha-1-antitrypsin (SERPINA1, PI; 107400) is a classic member of this family. Neuroserpin was first identified as a protein secreted from the axons of dorsal root ganglion neurons (Stoeckli et al., 1989). It is expressed in the late stages of neurogenesis during the process of synapse formation.
Schrimpf et al. (1997) cloned human neuroserpin, symbolized PI12, from fetal and retina cDNA libraries. The PI12 gene encodes a 410-amino acid polypeptide with 80% identity to chicken neuroserpin and 21 to 35% identity to other serpin family members. The nearest homolog of PI12 is protease inhibitor-7 (177010). The neuroserpin sequence contains the reactive center loop characteristic of serpins. By Northern blotting, Schrimpf et al. (1997) showed that the PI12 gene is expressed as a 1.8-kb transcript, predominantly in the brain.
Schrimpf et al. (1997) used fluorescence in situ hybridization to map the PI12 gene to chromosome 3q26.
Neuroserpin is a typical member of the serpins, a family of serine proteinase inhibitors that share a tightly conserved tertiary structure. The inhibitory function of the serpins depends on their ability to undergo a profound conformational transition, involving an opening of the main 5-stranded sheet of the molecule and allowing the insertion of the reactive centre loop as an extra middle strand (Davis et al., 1999).
In affected members of 2 unrelated families with familial encephalopathy with neuroserpin inclusion bodies (FENIB; 604218), Davis et al. (1999) identified 2 different heterozygous mutations in the PI12 gene (S49P; 602445.0001 and S52R; 602445.0002, respectively). Both mutations occur in the shutter region of the protein and disrupt the sheet-opening mechanism crucial to neuroserpin stability, resulting in formation of intermolecular linkages, loop-sheet polymers, and neuroserpin aggregate inclusions. These pathologic changes were similar to those observed in alpha-1-antitrypsin deficiency (see 107400) and inclusion bodies in hepatic cirrhosis.
Molinari et al. (2003) reviewed the molecular pathogenesis of FENIB caused by mutations in neuroserpin.
Davis et al. (2002) reported 2 families with FENIB associated with heterozygous mutations in the PI12 gene (H338R; 602445.0003 and G392E; 602445.0004, respectively). Examination of frontal cortex tissue from these probands and those reported by Davis et al. (1999), Davis et al. (2002) showed that the amount of inclusions correlated with the severity of disease and age of onset, as well as with the predicted conformational instability on the crystallographic structure of the protein. The most severely disrupted mutation, G392E, resulted in a near 10-fold increase in inclusions, with onset at age 13 years and death by age 19. The mutation least prone to polymerize, S49P, was associated with onset of dementia late in middle age.
In the larger of 2 families with familial encephalopathy with neuroserpin inclusion bodies (FENIB; 604218) studied by them, Davis et al. (1999) described a T-to-C transition at nucleotide 226 of the PI12 gene, resulting in a ser49-to-pro (S49P) substitution in the shutter domain of the protein. Davis et al. (1999) referred to this mutation as PI12 Syracuse. The mutation created a MnlI restriction site. The mutation was identified in 14 individuals of 38 family members screened, and was not detected upon screening 120 chromosomes from 60 unrelated Caucasian individuals. Individuals with the S49P mutation presented clinically around the fifth decade of life with cognitive decline, including deficits in attention and concentration, response regulation difficulties, and impaired visuospatial skills.
In in vitro studies, Belorgey et al. (2002) found that mutant S49P serpin formed unstable complexes with tissue plasminogen activator (TPA; 173370), had lower melting temperature, and more readily formed loop-sheet polymers under physiologic conditions compared to the wildtype protein. The data indicated that S49P neuroserpin is a poor proteinase inhibitor and readily forms loop-sheet polymers, providing strong support for the role of neuroserpin polymerization in the formation of the intraneuronal inclusions that are characteristic of FENIB.
In COS-7 cells, Miranda et al. (2004) showed that both the S49P and S52R (602445.0002) mutant proteins were retained in the endoplasmic reticulum as polymers, in contrast to the wildtype protein that was secreted. The S52R mutant showed faster accumulation and slower secretion compared to S49P, consistent with the more severe clinical phenotype associated with the S52R mutation.
In the smaller of 2 families with familial encephalopathy with neuroserpin inclusion bodies (FENIB; 604218) studied by them, Davis et al. (1999) described a point mutation in the PI12 gene that caused a ser52-to-arg (S52R) substitution. Davis et al. (1999) designated this mutation PI12 Portland and found it in a mother and her older child, but not in 2 unaffected family members, with FENIB. The clinical presentation was in the second or third decade of life, with epilepsy and progressive cognitive decline ending in institutionalization. Davis et al. (1999) stated the clinical presentation of the FENIB families closely matched the severity of their individual mutations. The domain controlling the opening of the main sheet of the molecule is centered on serine-49 in neuroserpin, and the conserved serine-52 forms an even more critical interaction with the sheet. In keeping with the predicted gradation in severity of the molecular lesions, neurodegeneration presented some 20 years earlier in the family with S52R than in the family with S49P (602445.0001).
Takao et al. (2000) identified heterozygosity for the S52R mutation in 2 brothers with progressive myoclonic epilepsy and dementia. The proband developed seizures at age 24, which progressed to status epilepticus over several years. He also developed slow speech, diplopia, nystagmus, dysarthria, and myoclonus in the extremities. He had rapid development of dementia at age 28, was institutionalized at age 32, and died at age 43 from aspiration pneumonia. Detailed neuropathologic examination showed neuronal loss, gliosis, and widespread eosinophilic intraneuronal PI12-immunoreactive inclusion bodies in the cerebral cortex, substantia nigra, and other areas of the central nervous system. Their deceased mother was reportedly similarly affected.
In a 23-year-old man with an 8-year history of progressive myoclonic epilepsy, dementia, tremor, and dysarthria (FENIB; 604218), Davis et al. (2002) identified a 1013A-G transition in the PI12 gene, resulting in a his338-to-arg (H338R) substitution in the shutter region, which is important for the conformational stability of the molecule. There were no other affected family members.
In a 13-year-old girl developed progressive myoclonus epilepsy with intractable seizures, myoclonus, and dementia (FENIB; 604218), Davis et al. (2002) identified a 1175G-A transition in the PI12 gene, resulting in a gly392-to-glu (G392E) substitution in the shutter region, which is important for the conformational stability of the molecule. She died at age 19 years during status epilepticus. Her father was said to be mentally deficient, and a paternal uncle had died from epilepsy at 18 years of age.
In an 11-year-old girl with severe epilepsy and cognitive decline (FENIB; 604218), Coutelier et al. (2008) identified a heterozygous de novo 1174A-G transition in exon 9 of the PI12 gene, resulting in a gly392-to-arg (G392R) substitution. Coutelier et al. (2008) noted that this residue was affected in another patient with a severe form of the disorder (G392E; 602445.0004), and suggested that mutations in exon 9 of the PI12 gene result in more severe conformational changes.
Belorgey, D., Crowther, D. C., Mahadeva, R., Lomas, D. A. Mutant neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro. J. Biol. Chem. 277: 17367-17373, 2002. [PubMed: 11880376] [Full Text: https://doi.org/10.1074/jbc.M200680200]
Coutelier, M., Andries, S., Ghariani, S., Dan, B., Duyckaerts, C., van Rijckevorsel, K., Raftopoulos, C., Deconinck, N., Sonderegger, P., Scaravilli, F., Vikkula, M., Godfraind, C. Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep. Neurology 71: 64-66, 2008. [PubMed: 18591508] [Full Text: https://doi.org/10.1212/01.wnl.0000316306.08751.28]
Davis, R. L., Shrimpton, A. E., Carrell, R. W., Lomas, D. A., Gerhard, L., Baumann, B., Lawrence, D. A., Yepes, M., Kim, T. S., Ghetti, B., Piccardo, P., Takao, M., Lacbawan, F., Muenke, M., Sifers, R. N., Bradshaw, C. B., Kent, P. F., Collins, G. H., Larocca, D., Holohan, P. D. Association between conformational mutations in neuroserpin and onset and severity of dementia. Lancet 359: 2242-2247, 2002. Note: Erratum: Lancet 360: 1102 only, 2002. [PubMed: 12103288] [Full Text: https://doi.org/10.1016/S0140-6736(02)09293-0]
Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, D., Collins, G. H., Sonderegger, P., Kinter, J., Becker, L. M., Lacbawan, F., Krasnewich, D., Muenke, M., Lawrence, D. A., Yerby, M. S., Shaw, C.-M., Gooptu, B., Elliott, P. R., Finch, J. T., Carrell, R. W., Lomas, D. A. Familial dementia caused by polymerization of mutant neuroserpin. Nature 401: 376-379, 1999. [PubMed: 10517635] [Full Text: https://doi.org/10.1038/43894]
Miranda, E., Romisch, K., Lomas, D. A. Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum. J. Biol. Chem. 279: 28283-28291, 2004. [PubMed: 15090543] [Full Text: https://doi.org/10.1074/jbc.M313166200]
Molinari, F., Meskanaite, V., Munnich, A., Sonderegger, P., Colleaux, L. Extracellular proteases and their inhibitors in genetic diseases of the central nervous system. Hum. Molec. Genet. 12: R195-R200, 2003. [PubMed: 12925575] [Full Text: https://doi.org/10.1093/hmg/ddg276]
Schrimpf, S. P., Bleiker, A. J., Brecevic, L., Kozlov, S. V., Berger, P., Osterwalder, T., Krueger, S. R., Schinzel, A., Sonderegger, P. Human neuroserpin (PI12): cDNA cloning and chromosomal localization to 3q26. Genomics 40: 55-62, 1997. [PubMed: 9070919] [Full Text: https://doi.org/10.1006/geno.1996.4514]
Stoeckli, E. T., Lemkin, P. F., Kuhn, T. B., Ruegg, M. A., Heller, M., Sonderegger, P. Identification of proteins secreted from axons of embryonic dorsal-root-ganglia neurons. Europ. J. Biochem. 180: 249-258, 1989. [PubMed: 2924765] [Full Text: https://doi.org/10.1111/j.1432-1033.1989.tb14640.x]
Takao, M., Benson, M. D., Murrell, J. R., Yazaki, M., Piccardo, P., Unverzagt, F. W., Davis, R. L., Holohan, P. D., Lawrence, D. A., Richardson, R., Farlow, M. R., Ghetti, B. Neuroserpin mutation S52R causes neuroserpin accumulation in neurons and is associated with progressive myoclonus epilepsy. J. Neuropath. Exp. Neurol. 59: 1070-1086, 2000. [PubMed: 11138927] [Full Text: https://doi.org/10.1093/jnen/59.12.1070]