Alternative titles; symbols
HGNC Approved Gene Symbol: PNKD
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:218,270,519-218,346,793 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Paroxysmal nonkinesigenic dyskinesia 1 | 118800 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Hirosawa et al. (1999) cloned KIAA1184. The transcript contains a repetitive sequence in the 3-prime UTR, and the deduced 380-amino acid protein shares 43% identity over 260 amino acids with human hydroxyacylglutathione hydrolase (HAGH; 138760). RT-PCR ELISA detected KIAA1184 expression in all tissues and specific brain regions examined. Highest expression was in adult brain, followed by fetal brain, skeletal muscle, and ovary, with lower expression in spleen, heart, testis, lung, liver, kidney, fetal liver, and pancreas. Specific brain regions showed intermediate to high expression, with the highest level in cerebellum.
By PCR of human fetal brain cDNA, Lee et al. (2004) cloned 3 alternatively spliced MR1 transcripts, which they called MR1L, MR1M, and MR1S and which consist of 10 exons, 9 exons, and 3 exons, respectively. Exons 1 and 2 are shared by MR1L and MR1S, and MR1S has a unique 3-prime exon encoding 63 amino acids. Exons 3 to 10 are common to MR1L and MR1M, and MR1M has a unique 5-prime exon encoding 56 amino acids. MR1L and MR1M contain an N-terminal transmembrane domain and a beta-lactamase domain. Northern blot analysis detected ubiquitous expression of MR1S in peripheral tissues and all brain regions examined, and MR1L was expressed exclusively in brain regions. In HEK293 cells, MR1L localized to the cell membrane. MR1M localized specifically to the perinuclear region, and MR1S was found throughout the cytoplasm and in the nucleus. Rainier et al. (2004) noted that MR1L results in a 385-amino acid protein with a molecular mass of 42.9 kD and that MR1M results in a 361-amino acid protein with a molecular mass of 40.7 kD.
Shen et al. (2011) found that MR1 localized to the cell membrane and to late endosomes in human neuroblastoma SH-SY5Y cells. MR1 did not localize to the mitochondria in COS-7 cells.
Lee et al. (2004) determined that the MR1 gene contains 12 exons.
Stumpf (2025) mapped the PNKD gene to chromosome 2q35 based on an alignment of the PNKD sequence (GenBank BC036457) with the genomic sequence (GRCh38).
The beta-lactamase domain of MR1 shows similarities to HAGH (138760). However, in cells and Drosophila, Shen et al. (2011) found that the long isoform of MR1 could not effectively restore absent HAGH activity, suggesting that MR1 does not hydrolyze S-D-lactoyl-glutathione (SLG) at appreciable levels in vivo. Mr1-null mice had decreased levels of glutathione in the frontal cortex compared to wildtype mice, suggesting that some glutathione-related metabolic changes are present. Shen et al. (2011) hypothesized that the long isoform of MR1 may function in a pathway to detoxify an alpha-ketonaldehyde product using glutathione as a cofactor in neuronal cells. Since glutathione is essential for maintaining proper cellular redox status, reduced glutathione levels in cells with mutant MR1 may render them more susceptible to oxidative stress.
In affected members of 2 unrelated families with autosomal dominant paroxysmal dystonic choreoathetosis (PDC), also known as paroxysmal nonkinesigenic dyskinesia-1 (PNKD1; 118800), Rainier et al. (2004) identified 2 different heterozygous mutations in exon 1 of the MR1 gene (A9V, 609023.0001; A7V, 609023.0002).
Lee et al. (2004) identified the A9V mutation in affected members of 3 unrelated families with PNKD1 and the A7V mutation in affected members of 5 unrelated families with PNKD1. They noted that MR1L is likely to have similar enzymatic activity to HAGH, which functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a byproduct of oxidative stress. Lee et al. (2004) suggested a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD1.
Ghezzi et al. (2009) reported a 3-generation PNKD family in which the proband was heterozygous for a mutation (A33P; 609023.0003) in the MR1 gene. By immunofluorescence microscopy and Western blot analysis, they studied the subcellular localization of both wildtype and mutant MR1 isoforms. The mutation-free MR1M isoform was localized in the Golgi apparatus, ER, and plasma membrane, whereas both MR1L and MR1S isoforms were mitochondrial proteins, imported into the organelle via the 39-amino acid N-terminal mitochondrial targeting sequence (MTS). All 3 known MR1 mutations are contained within the MTS. The authors showed that the MTS was cleaved off the mature MR1L and MR1S isoforms before their insertion in the inner mitochondrial membrane. Therefore, mature MR1S and MR1L of PNKD patients are identical to those of normal subjects. There was no difference in import efficiency and protein maturation between wildtype and mutant MR1 variants. Ghezzi et al. (2009) concluded that PNKD is due to a novel disease mechanism based on a deleterious action of the MTS.
Shen et al. (2011) demonstrated that the N terminus of wildtype MR1 is cleaved, and that this normal cleavage is blocked by disease-causing mutations in the MR1 gene. Cellular studies showed that the mutant long isoform of MR1 was degraded faster than the wildtype protein. Transgenic mice with the mutant long isoform had decreased levels of mutant protein compared to wildtype, although transcript levels were normal. The findings suggested that impaired protein cleavage was associated with decreased protein stability.
In 8 affected members of a large Polish-American family with PNKD1 (118800) originally reported by Fink et al. (1996), Rainier et al. (2004) identified a heterozygous 72C-T transition in exon 1 of the MR1 gene, resulting in an ala9-to-val (A9V) substitution. The mutation occurs in a conserved N-terminal alpha helix of the protein and was not identified in 105 controls. Two unaffected family members also carried the mutation, indicating reduced penetrance of the disorder.
In affected members of 3 unrelated families with PNKD1, Lee et al. (2004) identified the A9V mutation. The mutation was not present in over 250 unrelated controls.
In affected members of a family with PNKD1 originally reported by Raskind et al. (1998), Chen et al. (2005) identified the A9V substitution. Haplotype analysis suggested that the mutation arose independently from that found in the family reported by Rainier et al. (2004).
Djarmati et al. (2005) identified the A9V mutation in a 15-year-old Serbian boy with PNKD1. The patient belonged to a large family with 12 additional affected members in 5 successive generations. Three obligate mutation carriers were unaffected, suggesting incomplete penetrance.
In 4 affected members of a family with PNKD1 (118800), Rainier et al. (2004) identified a heterozygous 66C-T transition in exon 1 of the MR1 gene, resulting in an ala7-to-val (A7V) substitution. The mutation occurs in a conserved N-terminal alpha helix of the protein and was not identified in 105 controls.
In affected members of 5 unrelated families with PNKD1, Lee et al. (2004) identified the A7V mutation. The mutation was not present in over 250 unrelated controls.
In affected members of a large PNKD1 family of French and Irish origin, Chen et al. (2005) identified the A7V substitution. Haplotype analysis suggested that the mutation arose independently from that found in the family reported by Rainier et al. (2004).
In the affected proband of a 3-generation family with PNKD1 (118800), Ghezzi et al. (2009) identified heterozygosity for a 97G-C transversion in exon 2 of the MR1 gene, resulting in an ala33-to-pro (A33P) substitution in a conserved residue of the N-terminal mitochondrial targeting sequence. The mutation was not identified in 500 control chromosomes.
Chen, D.-H., Matsushita, M., Rainier, S., Meaney, B., Tisch, L., Feleke, A., Wolff, J., Lipe, H., Fink, J., Bird, T. D., Raskind, W. H. Presence of alanine-to-valine substitutions in myofibrillogenesis regulator 1 in paroxysmal nonkinesigenic dyskinesia. Arch. Neurol. 62: 597-600, 2005. [PubMed: 15824259] [Full Text: https://doi.org/10.1001/archneur.62.4.597]
Djarmati, A., Svetel, M., Momcilovic, D., Kostic, V., Klein, C. Significance of recurrent mutations in the myofibrillogenesis regulator 1 gene. (Letter) Arch. Neurol. 62: 1641 only, 2005. [PubMed: 16216955] [Full Text: https://doi.org/10.1001/archneur.62.10.1641-a]
Fink, J. K., Rainier, S., Wilkowski, J., Jones, S. M., Kume, A., Hedera, P., Albin, R., Mathay, J., Girbach, L., Varvil, T., Otterud, B., Leppert, M. Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q. Am. J. Hum. Genet. 59: 140-145, 1996. [PubMed: 8659518]
Ghezzi, D., Viscomi, C., Ferlini, A., Gualandi, F., Mereghetti, P., DeGrandis, D., Zeviani, M. Paroxysmal non-kinesigenic dyskinesia is caused by mutation of the MR-1 mitochondrial targeting sequence. Hum. Molec. Genet. 18: 1058-1064, 2009. [PubMed: 19124534] [Full Text: https://doi.org/10.1093/hmg/ddn441]
Hirosawa, M., Nagase, T., Ishikawa, K., Kikuno, R., Nomura, N., Ohara, O. Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. DNA Res. 6: 329-336, 1999. [PubMed: 10574461] [Full Text: https://doi.org/10.1093/dnares/6.5.329]
Lee, H.-Y., Xu, Y., Huang, Y., Ahn, A. H., Auburger, G. W. J., Pandolfo, M., Kwiecinski, H., Grimes, D. A., Lang, A. E., Nielsen, J. E., Averyanov, Y., Servidei, S., Friedman, A., Van Bogaert, P., Abramowicz, M. J., Bruno, M. K., Sorensen, B. F., Tang, L., Fu, Y.-H., Ptacek, L. J. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum. Molec. Genet. 13: 3161-3170, 2004. [PubMed: 15496428] [Full Text: https://doi.org/10.1093/hmg/ddh330]
Rainier, S., Thomas, D., Tokarz, D., Ming, L., Bui, M., Plein, E., Zhao, X., Lemons, R., Albin, R., Delaney, C., Alvarado, D., Fink, J. K. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch. Neurol. 61: 1025-1029, 2004. [PubMed: 15262732] [Full Text: https://doi.org/10.1001/archneur.61.7.1025]
Raskind, W. H., Bolin, T., Wolff, J., Fink, J., Matsushita, M., Litt, M., Lipe, H., Bird, T. D. Further localization of a gene for paroxysmal dystonic choreoathetosis to a 5-cM region on chromosome 2q34. Hum. Genet. 102: 93-97, 1998. [PubMed: 9490305] [Full Text: https://doi.org/10.1007/s004390050659]
Shen, Y., Lee, H.-Y., Rawson, J., Ojha, S., Babbitt, P., Fu, Y.-H., Ptacek, L. J. Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability. Hum. Molec. Genet. 20: 2322-2332, 2011. [PubMed: 21487022] [Full Text: https://doi.org/10.1093/hmg/ddr125]
Stumpf, A. M. Personal Communication. Baltimore, Md. 2/28/2025.