Alternative titles; symbols
HGNC Approved Gene Symbol: PDYN
SNOMEDCT: 718772002;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:1,978,756-1,994,285 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | Spinocerebellar ataxia 23 | 610245 | Autosomal dominant | 3 |
The PDYN gene encodes prodynorphin, the precursor protein for several opioid neuropeptides (Horikawa et al., 1983).
Horikawa et al. (1983) cloned a human genomic DNA segment containing the preproenkephalin B gene. From studies of the gene for porcine preproenkephalin B, it is known to contain the determinants for neoendorphin, dynorphin, and leumorphin (containing rimorphin in its amino-terminus). These opioid peptides, each with a leucine-enkephalin structure, act on the kappa-receptor.
Horikawa et al. (1983) found that the structural organization of the PDYN gene resembles that of the genes encoding the other opioid peptide precursors, preproenkephalin A (PENK; 131330) and preproopiomelanocortin (POMC; 176830).
Zhu et al. (2003) found that the relative position of each of 460 putative coding orthologs of the PDYN gene was the same in human and mouse, except for a single genomic segment rearrangement. This similarity extended to exon/intron structure, the size of introns, as well as strong evidence for the conservation of position of ancient LINE-1, LINE-2, and LTR repetitive sequence. There was also evidence for conservation of a limited amount of noncoding single-copy sequence.
Gong et al. (2003) described a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes, and pathways. They found that clusters of medium spiny neurons that project to the substantia nigra were revealed in Pdyn BAC transgenic mice. These cells corresponded to the striatal patches that have been documented in a number of anatomic studies in the developing and adult striatum.
Litt et al. (1987, 1988) assigned the PDYN gene to human chromosome 20 by Southern blot analysis of DNAs from a rodent-human somatic cell hybrid panel. In situ hybridization to metaphase chromosomes confirmed this assignment and indicated the regional localization to be 20pter-p12.
Summar et al. (1990) demonstrated very close linkage of PDYN with ARVP (192340) and OT (167050); no recombinants were found with a lod score of 5.2. This cluster of genes appears to be located about 15 cM distal to D20S5, which is located near the middle of the short arm at 20p12.21. In connection with this close proximity of the genes, it is noteworthy that the ARVP and PDYN peptides are coexcreted in the same neurosecretory granules of some pituitary axons and that increased transcription of both genes occurs with osmotic stimulation.
In a study of sequence homology between human chromosome 20 and the mouse genome, Zhu et al. (2003) determined that the Pdyn gene is located on mouse chromosome 2.
Zimprich et al. (2000) described a polymorphism of the PDYN gene promoter: 1 to 4 repeats of a 68-bp element containing 1 binding site per repeat for the transcription factor AP1 (165160). Upon activation of the AP1 complex, H alleles (3 or 4 repeats) were associated with a significant increase in gene expression in a CAT reporter gene assay, whereas L alleles could not be stimulated over basal conditions.
Stogmann et al. (2002) performed a case-control association study in 155 patients with nonlesional temporal lobe epilepsy (see 608096) and 202 controls, and found that the PDYN promoter low-expression L alleles (1 or 2 repeats) conferred an increased risk for temporal lobe epilepsy in patients with a family history for seizures. Irrespective of the familial background, L homozygotes displayed a higher risk for secondarily generalized seizures and status epilepticus. Comparing 182 nonlesional patients with temporal lobe epilepsy and 205 ethnically matched controls, Tilgen et al. (2003) failed to find an association between the L allele and increased risk for temporal lobe epilepsy, tonic-clonic seizures, status epilepticus, clustering of seizures, or febrile convulsions.
Spinocerebellar Ataxia 23
In affected members of a family with autosomal dominant spinocerebellar ataxia-23 (SCA23; 610245) reported by Verbeek et al. (2004), Bakalkin et al. (2010) identified a heterozygous mutation in the PDYN gene (R138S; 131340.0001). Screening of 1,100 additional Dutch ataxia patients revealed 3 more mutations: 1 in 2 sibs (R215C; 131340.0002) and 1 each in 2 additional unrelated patients with no family history of the disorder (L211S, 131340.0003 and R212W, 131340.0004, respectively). These findings indicated that SCA23 is an uncommon cause of SCA (0.5%) in the Dutch population. Cellular studies and studies on patient cerebellar tissue implicated 2 possible pathogenic mechanisms: upregulation of dynorphin A, which may have neurodegenerative effects or cause changes in opioid activity, or accumulation of mutant PDYN that cannot be properly processed and is toxic to Purkinje cells.
King and Wilson (1975) argued that human evolution owes more to change in gene regulation than to changes in gene structure. While divergence in gene complement and amino acid sequence are discernible from genome sequences, functional divergence in cis-regulatory regions is largely invisible in sequence data. Given the difficulties associated with identifying DNA sequence changes responsible for changes in inducibility, Rockman et al. (2005) focused on a candidate region whose role in inducibility in humans had already been demonstrated. They studied the cis-regulatory evolution of the PDYN gene, and investigated the functional consequences of species differences experimentally by transient transfection of promoter-reporter constructs into cultured human cells. The PDYN gene encodes prodynorphin, the precursor molecule for a suite of endogenous opioids in neuropeptides with critical roles in regulating perception, behavior, and memory. Rockman et al. (2005) presented independent lines of phylogenetic and population genetic evidence supporting a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee-human hybrid promoters in cultured cells, the selected sequence increased transcriptional inducibility. The authors concluded that the evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.
In affected members of a Dutch family with autosomal dominant spinocerebellar ataxia-23 (SCA23; 610245), Bakalkin et al. (2010) identified a heterozygous 414G-T transversion in exon 4 of the PDYN gene, resulting in an arg138-to-ser (R138S) substitution in a nonconserved residue of the nonopioid domain. The mutation was not found in 1,000 control chromosomes. The age at onset ranged from 43 to 56 years, and the disorder was characterized by slowly progressive gait and limb ataxia, variable dysarthria, slow saccades, ocular dysmetria, and decreased vibratory sense below the knees. Four affected individuals showed hyperreflexia, 2 of whom also had extensor plantar responses. Postmortem examination of 1 patient showed severe cerebellar atrophy. Immunohistochemical studies of cerebellum derived from 1 patient with the R138S mutation showed that PDYN, dynorphin A, and dynorphin B were located in Purkinje cells as observed in control cerebellum, but cerebellar tissue with the mutation had decreased levels of EAAT4 (SLC1A6; 600636) and calbindin (CALB1; 114050), both of which are markers of Purkinje cells. SLC1A6 was accumulated and aggregated in patient cerebellar tissue. These changes in SLC1A6 suggested a defect in glutamate signaling.
In 2 Dutch sibs with spinocerebellar ataxia-23 (610245), Bakalkin et al. (2010) identified a heterozygous 643C-T transition in the PDYN gene, resulting in an arg215-to-cys (R215C) substitution in a conserved residue of the dynorphin A sequence. Clinical features included onset in the fifties of head and postural tremor, mild dysarthria, and mild ataxia. The sister had peripheral sensory neuropathy and mild cognitive decline, whereas the brother had instability of ocular gaze fixation. Transfection of the mutation into rat insulinoma cells showed that the mutant PDYN protein was produced, but processing to opioid peptides was dramatically affected, resulting in an approximately 2-fold decreased level of dynorphin B compared to dynorphin A. Mutant dynorphin A was neurotoxic to cultured rodent striatal neurons, suggesting a dominant-negative effect.
In a Dutch man with SCA23 (610245), Bakalkin et al. (2010) identified a heterozygous 632T-C transition in the PDYN gene, resulting in a leu211-to-ser (L211S) substitution in a conserved residue of the dynorphin A sequence. The patient had onset at age 73 years of progressive gait and upper limb ataxia, oculomotor abnormalities, distal sensory neuropathy, and pyramidal signs of the legs. He also had subtle parkinsonian features. There was no apparent family history of the disorder. Transfection of the mutation into rat insulinoma cells showed that the mutant PDYN protein was produced, but processing to opioid peptides was dramatically affected, with increased levels of dynorphin A compared to dynorphin B. These results suggested slow conversion of dynorphin A to short enkephalins. However, mutant L211S dynorphin A was not neurotoxic to cultured rodent striatal neurons.
In a Dutch patient with SCA23 (610245), Bakalkin et al. (2010) identified a heterozygous 634C-T transition in the PDYN gene, resulting in an arg212-to-trp (R212W) substitution in a conserved residue of the dynorphin A sequence. Brain MRI showed generalized cerebral cortical and subcortical atrophy, agenesis of the corpus callosum, and prominent atrophy of the cerebellar vermis, the pons, and the inferior olivary nucleus. Transfection of the mutation into rat insulinoma cells showed that the mutant PDYN protein was produced, but processing to opioid peptides was dramatically affected, with increased levels of dynorphin A compared to dynorphin B. These results suggested slow conversion of dynorphin A to short enkephalins. Mutant dynorphin A was neurotoxic to cultured rodent striatal neurons, suggesting a dominant-negative effect.
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Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., Heintz, N. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425: 917-925, 2003. [PubMed: 14586460] [Full Text: https://doi.org/10.1038/nature02033]
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Rockman, M. V., Hahn, M. W., Soranzo, N., Zimprich, F., Goldstein, D. B., Wray, G. A. Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol. 3: e387, 2005. Note: Electronic Article. [PubMed: 16274263] [Full Text: https://doi.org/10.1371/journal.pbio.0030387]
Stogmann, E., Zimprich, A., Baumgartner, C., Aull-Watschinger, S., Hollt, V., Zimprich, F. A functional polymorphism in the prodynorphin gene promoter is associated with temporal lobe epilepsy. Ann. Neurol. 51: 260-263, 2002. [PubMed: 11835385] [Full Text: https://doi.org/10.1002/ana.10108]
Summar, M. L., Phillips, J. A., III, Battey, J., Castiglione, C. M., Kidd, K. K., Maness, K. J., Weiffenbach, B., Gravius, T. C. Linkage relationships of human arginine vasopressin-neurophysin-II and oxytocin-neurophysin-I to prodynorphin and other loci on chromosome 20. Molec. Endocr. 4: 947-950, 1990. [PubMed: 1978246] [Full Text: https://doi.org/10.1210/mend-4-6-947]
Tilgen, N., Rebstock, J., Horvath, S., Propping, P., Elger, C. E., Heils, A. Prodynorphin gene promoter polymorphism and temporal lobe epilepsy. (Letter) Ann. Neurol. 53: 280-281, 2003. [PubMed: 12557303] [Full Text: https://doi.org/10.1002/ana.10457]
Verbeek, D. S., van de Warrenburg, B. P., Wesseling, P., Pearson, P. L., Kremer, H. P., Sinke, R. J. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3. Brain 127: 2551-2557, 2004. [PubMed: 15306549] [Full Text: https://doi.org/10.1093/brain/awh276]
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Zimprich, A., Kraus, J., Woltje, M., Mayer, P., Rauch, E., Hollt, V. An allelic variation in the human prodynorphin gene promoter alters stimulus-induced expression. J. Neurochem. 74: 472-477, 2000. [PubMed: 10646497] [Full Text: https://doi.org/10.1046/j.1471-4159.2000.740472.x]