Alternative titles; symbols
HGNC Approved Gene Symbol: DPP6
Cytogenetic location: 7q36.2 Genomic coordinates (GRCh38): 7:153,748,133-154,894,285 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.2 | {Ventricular fibrillation, paroxysmal familial, 2} | 612956 | Autosomal dominant | 3 |
| Intellectual developmental disorder, autosomal dominant 33 | 616311 | Autosomal dominant | 3 |
DPP6 is an auxiliary subunit of Kv4 (see 300281)-containing A-type K+ channels that regulate excitability and plasticity of neurons and other excitable cells (Lin et al., 2018).
Wada et al. (1992) isolated cDNA clones for a dipeptidyl peptidase IV-related protein from bovine and rat brain libraries. Unlike dipeptidyl peptidase IV (102720) which belongs to a family in which a serine, an aspartate, and a histidine form a catalytic triad, the DPPIV-related protein does not show the first serine residue. Yokotani et al. (1993) isolated the human homolog.
Sun et al. (2011) reported that Dpp6-null mice lacked the A-type K+ current gradient critical for regulation of dendritic excitability in CA1 hippocampal neurons. Loss of Dpp6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-knockout recordings, indicating compartmentalized regulation of neuronal excitability.
Liao et al. (2013) stated that the DPP6 gene comprises 26 exons.
Using a fragment of the bovine DPPX clone as a probe, Yokotani et al. (1993) mapped the human DPP6 gene to chromosome 7 by PCR analysis of somatic cell hybrids. Wada et al. (1993) showed that the mouse Dpp6 gene is linked to markers in the proximal end of chromosome 5 in a region of conserved synteny.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including DPPX, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Familial Paroxysmal Ventricular Fibrillation
In 3 related Dutch families segregating for idiopathic ventricular fibrillation (VF2; 612956), Alders et al. (2009) mapped the disease locus to a segment of chromosome 7 that includes the DPP6 gene. Direct sequencing of the probands in these 3 families as well as in 42 other Dutch probands segregating IVF identified no mutations in the coding sequences of DPP6, but a C-to-T transition 340 bases upstream from the ATG initiation codon of isoform 2 of DPP6 (612956.0001) was identified in the 3 related probands and in 7 others. The -340C-T variant was not present in a control group of 350 Dutch individuals of European descent. Alders et al. (2009) demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls. Clinical evaluation of 84 risk-haplotype carriers and 71 noncarriers revealed no ECG or structural parameters indicative of cardiac disease. Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years. Alders et al. (2009) proposed increased DDP6 expression as the likely pathogenetic mechanism of VF in these families.
Autosomal Dominant Intellectual Developmental Disorder 33
Liao et al. (2013) conducted a copy number variation analysis of the DPP6 gene in patients with autosomal dominant microcephaly and variable mental retardation. The analysis was performed on DNA samples from 22 patients with microcephaly using high-resolution, array-based genomic hybridization. Two patients with small de novo deletions in the DPP6 gene were identified. Sequence analysis was also performed in another 50 microcephalic patients. A missense mutation in the DPP6 gene (M385L; 126141.0002) was identified in a family segregating microcephaly and autosomal dominant mental retardation. In mice, knockdown of Dpp6 using short hairpin RNA (shRNA) resulted in smaller brains and learning disabilities compared to wildtype littermates.
Sun et al. (2011) generated Dpp6-knockout mice by deletion of exon 2. These mice displayed a total loss of Dpp6 mRNA and protein. The authors also showed that the closely related family member Dpp10 (608209), which is not normally expressed in pyramidal dendrites, is not upregulated in these cells in Dpp6-knockout mice. These mice lacked a dendritic A-type K+ current gradient, and the remaining A-type K+ channels in Dpp6-knockout dendrites were mediated by Kv4 (see KCND1, 300281).
Liao et al. (2013) found that mice with knockdown of transcript 1 of Dpp6 had smaller brains than their wildtype littermates. Performance on the standard Morris water maze indicated spatial memory defects and learning disabilities.
Lin et al. (2018) found that Dpp6 -/- mice had significantly lower body and brain weights compared with wildtype and showed deficits in various learning and memory tasks. Analysis with Dpp6 -/- cultured neurons revealed developmental deficits in synaptic formation and stabilization, and microscopic analysis demonstrated synaptic structure deficits in the hippocampal CA1 region of adult Dpp6 -/- mice.
In 3 related families from the Netherlands and an additional 7 of 42 probands with idiopathic ventricular fibrillation (VF2; 612956) from the Netherlands, Alders et al. (2009) identified a C-to-T transition 340 bases upstream from the ATG start site of isoform 2 of DPP6 (rs3807218). All 10 probands carried the same haplotype. The variant was not present in a control group of 350 Dutch individuals of European descent. The variant is associated with 20-fold increased expression in DPP6 mRNA levels in the myocardium of carriers as compared to controls.
In a 5-year-old girl (BY2950) from a family segregating autosomal dominant mental retardation and microcephaly (MRD33; 616311), Liao et al. (2013) identified a c.1153A-C transversion (c.1153A-C, NM_130797) in the DPP6 gene, resulting in a met385-to-leu (M385L) substitution. Her mother, maternal aunt, and grandfather were also affected. The mutation, which segregated with disease in the family, was not identified in 100 control chromosomes.
In a 12-year-old boy (BY0712) with microcephaly and mental retardation (MRD33; 616311), Liao et al. (2013) identified a de novo heterozygous 336-kb deletion in the DPP6 gene (chr7.153,649,777-153,985,995, GRCh37).
Alders, M., Koopmann, T. T., Christiaans, I., Postema, P. G., Beekman, L., Tanck, M. W. T., Zeppenfeld, K., Loh, P., Koch, K. T., Demolombe, S., Mannens, M. M. A. M., Bezzina, C. R., Wilde, A. A. M. Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation. Am. J. Hum. Genet. 84: 468-476, 2009. [PubMed: 19285295] [Full Text: https://doi.org/10.1016/j.ajhg.2009.02.009]
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027-1040, 2004. [PubMed: 15620360] [Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
Liao, C., Fu, F., Li, R., Yang, W., Liao, H., Yan, J., Li, J., Li, S., Yang, X., Li, D. Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation. Europ. J. Med. Genet. 56: 484-489, 2013. [PubMed: 23832105] [Full Text: https://doi.org/10.1016/j.ejmg.2013.06.008]
Lin, L., Murphy, J. G., Karlsson, R. M., Petralia, R. S., Gutzmann, J. J., Abebe, D., Wang, Y. X., Cameron, H. A., Hoffman, D. A. DPP6 loss impacts hippocampal synaptic development and induces behavioral impairments in recognition, learning and memory. Front. Cell. Neurosci. 12: 84, 2018. [PubMed: 29651237] [Full Text: https://doi.org/10.3389/fncel.2018.00084]
Sun, W., Maffie, J. K., Lin, L., Petralia, R. S., Rudy, B., Hoffman, D. A. DPP6 establishes the A-type K+ current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons. Neuron 71: 1102-1115, 2011. [PubMed: 21943606] [Full Text: https://doi.org/10.1016/j.neuron.2011.08.008]
Wada, K., Yokotani, N., Hunter, C., Doi, K., Wenthold, R. J., Shimasaki, S. Differential expression of two distinct forms of mRNA encoding members of a dipeptidyl aminopeptidase family. Proc. Nat. Acad. Sci. 89: 197-201, 1992. [PubMed: 1729689] [Full Text: https://doi.org/10.1073/pnas.89.1.197]
Wada, K., Zimmerman, K. L., Adamson, M. C., Yokotani, N., Wenthold, R. J., Kozak, C. A. Genetic mapping of the mouse gene encoding dipeptidyl aminopeptidase-like proteins. Mammalian Genome 4: 234-237, 1993. [PubMed: 8499659] [Full Text: https://doi.org/10.1007/BF00417570]
Yokotani, N., Doi, K., Wenthold, R. J., Wada, K. Non-conservation of a catalytic residue in a dipeptidyl aminopeptidase IV-related protein encoded by a gene on human chromosome 7. Hum. Molec. Genet. 2: 1037-1039, 1993. [PubMed: 8103397] [Full Text: https://doi.org/10.1093/hmg/2.7.1037]