Alternative titles; symbols
HGNC Approved Gene Symbol: DCDC2
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:24,171,755-24,383,292 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | ?Deafness, autosomal recessive 66 | 610212 | Autosomal recessive | 3 |
| Nephronophthisis 19 | 616217 | Autosomal recessive | 3 | |
| Sclerosing cholangitis, neonatal | 617394 | Autosomal recessive | 3 |
The DCDC2 gene encodes a protein containing 2 doublecortin peptide domains similar to those in the doublecortin gene (DCX; 300121) (Meng et al., 2005). DCDC2 plays a role in the inhibition of canonical WNT (164820) signaling (Schueler et al., 2015). DCDC2 is a ciliary protein that binds tubulin and enhances microtubule polymerization (summary by Girard et al., 2016).
By screening cells expressing both HLA-B7 and kidney tumor cell RNA with autologous cytolytic T cells, followed by PCR, van den Eynde et al. (1999) obtained cDNAs encoding RU2, which is identical to the KIAA1154 gene identified by Hirosawa et al. (1999). Genomic sequence analysis determined that RU2 is transcribed as a 'normal' gene, resulting in a sense transcript (RU2S), and in the opposite direction, resulting in a shorter antisense transcript (RU2AS; 608211) found in tumors. Testing of synthetic peptides determined that the tumor antigen binding to HLA-B7 has the sequence LPRWPPPQL. Northern blot analysis revealed that the full-length gene is expressed as a 2.2-kb transcript. RT-PCR analysis detected ubiquitous expression of the full-length RU2S transcript, but expression of the RU2AS transcript was restricted to normal kidney, bladder, liver, and testis, as well as tumors of various histologic origins. The deduced RU2S protein contains 476 amino acids, while the RU2AS protein contains 84 residues. Van den Eynde et al. (1999) concluded that potentially useful antigens for cancer immunotherapy cannot be predicted from the sequence of the normal cellular protein.
Using RT-PCR and Northern blot analysis, Schumacher et al. (2006) demonstrated that DCDC2 is expressed in the adult and fetal central nervous system (CNS).
Using quantitative real-time RT-PCR of human brain, Meng et al. (2005) showed that DCDC2 exhibited highest expression in entorhinal cortex, inferior temporal cortex, medial temporal cortex, hypothalamus, amygdala, and hippocampus.
Schueler et al. (2015) found that DCDC2 colocalized with acetylated alpha-tubulin (see TUBA1A, 602529) at the axoneme of primary cilia of human renal tubule cells and cholangiocytes in liver, and to multiciliated ependymal cells and pia mater cells in mouse brain. However, DCDC2 did not localize to the basal body.
In postnatal rat and mouse inner ear, Grati et al. (2015) found that Dcdc2 localized to the kinocilia of inner, outer, and vestibular hair cells and to the primary cilia of all supporting cell types. It localized along the entire length, with increasing concentrations toward the tip. Dcdc2 was found in association with the cellular microtubule network.
Girard et al. (2016) found expression of DCDC2 in the cytoplasm and in cilia of cholangiocytes in liver bile ducts. Grammatikopoulos et al. (2016) found expression of the DCDC2 gene in cuboidal cholangiocytes in smaller intrahepatic bile ducts, with only faint focal marking in columnar cholangiocytes of larger and extrahepatic bile ducts.
DCDC2 Intron 2 Short Tandem Repeat BV677278
Within intron 2 of the DCDC2 gene, Meng et al. (2005) identified a 168-bp purine-rich region containing a polymorphic compound short tandem repeat (STR) composed of 10 alleles containing variable copy numbers of (GAGAGGAAGGAAA)n and (GGAA)n repeat units. Database analysis identified 131 putative transcription factor binding sites distributed throughout the purine-rich region, including multiple copies of binding sites for the brain-related transcription factors PEAS3 (ETV4; 600711) and NFATP (NFATC2; 600490).
Using electrophoretic mobility shift assays, Meng et al. (2011) showed that the conserved polymorphic purine-rich STR in intron 2 of the DCDC2 gene, which they called BV677278, bound nuclear proteins in a human brain lysate as well as in lymphoma cells. Expression of the 6 most common alleles of BV677278 in P19 cells, multipotent murine cells that can differentiate into neurons and neuroglia, showed that the alleles have a range of DCDC2-specific enhancer activities. The findings suggested that BV677278 alleles can modify DCDC2 expression to various degrees, which may link to changes in neural migration in the central nervous system.
Using FISH, van den Eynde et al. (1999) mapped the DCDC2 gene to chromosome 6p22.1.
In cellular studies, Schueler et al. (2015) found that DCDC2 fully or partially colocalized with acetylated alpha-tubulin to the spindle microtubules during metaphase and anaphase; to the abscission structure during late telophase/diakinesis; and to the ciliary axoneme in ciliated cells during interphase. Throughout those cell-cycle phases, DCDC2 was excluded from the basal body (in interphase), the mitotic spindle poles (in metaphase and anaphase), and the midbody (in diakinesis). Coimmunoprecipitation studies showed that DCDC2 interacted with DVL1 (601365), DVL2 (602151), and DVL3 (601368). DCDC2 also interacted with JIP1 (MAPK8IP1; 604641), which mediates MAPK signaling. Knockdown of DCDC2 increased beta-catenin (CTNNB1; 116806)-induced activation of T cell factor (TCF)-dependent transcription, and overexpression of DCDC2 reduced TCF-dependent transcription. These findings suggested that DCDC2 normally inhibits WNT signaling, and that loss of DCDC2 results in constitutive activation of the WNT signaling pathway. Knockdown of DCDC2 in a kidney cell culture system resulted in significantly fewer cilia compared to control, but the kidney cells formed normal spheroids without severe changes in lumen formation. Treatment of the DCDC2-null cells with a Wnt inhibitor restored the cilia defects.
Nephronophthisis 19
In 2 unrelated patients with nephronophthisis-19 (NPHP19; 616217) with early-onset severe hepatic fibrosis, Schueler et al. (2015) identified homozygous or compound heterozygous truncating mutations in the DCDC2 gene (605755.0001-605755.0003). The mutation in the first patient was found by a combination of homozygosity mapping and whole-exome sequencing of 100 families with a similar disorder. The mutations in the subsequent patient were found by sequencing the DCDC2 gene in 800 families with a similar disorder. All mutations abrogated the normal inhibition of CTNNB1-induced activation of TCF-dependent transcription, resulting in increased WNT signaling. Cellular studies as well as studies in zebrafish showed that inhibition of the Wnt signaling pathway could rescue some of the defects associated with loss of dcdc2, suggesting a role for this pathway in the pathogenesis of NPHP19.
In a 13-year-old African Caribbean girl from Saint Vincent and the Grenadines with NPHP19, Slater et al. (2020) identified a homozygous nonsense mutation in the DCDC2 gene (S128X; 605755.0009). The DCDC2 gene was located in a 2.1-Mb area of homozygosity. In total, the patient was found to have 53 Mb of homozygosity, indicating identity by descent originating from a common ancestor between her parents. Functional studies were not performed.
Autosomal Recessive Deafness 66
In affected members of a consanguineous Tunisian family with autosomal recessive deafness-66 (DFNB66; 610212), Grati et al. (2015) identified a homozygous missense mutation in the DCDC2 gene (Q424P; 605755.0004). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Expression of mutant DCDC2a in hair cells and supporting cells caused cilium structural defects, and knockdown of the gene in zebrafish impaired hair cell survival and function.
Neonatal Sclerosing Cholangitis
In 4 patients from 2 unrelated consanguineous families with neonatal sclerosing cholangitis (NSC; 617394), Girard et al. (2016) identified 2 different homozygous mutations in the DCDC2 gene (605755.0005 and 605755.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed loss of DCDC2 immunostaining in the ciliary axoneme of liver cholangiocytes and fewer cilia on cholangiocytes, as well as abnormal accumulation of the mutant protein in the cytoplasm compared to controls.
In 7 patients from 6 unrelated families, many of Greek origin, with NSC, Grammatikopoulos et al. (2016) identified homozygous or compound heterozygous truncating mutations in the DCDC2 gene (see, e.g., 605755.0001; 605755.0002; 605755.0007; 605755.0008). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Parental DNA was only available for 1 patient, but the results confirmed segregation of the mutations with the disorder within the family. Patient liver samples showed absence of DCDC2 expression, consistent with a complete loss of function, as well as absence of normally constituted primary cilia in cholangiocytes. The patients were part of a cohort of 12 families with the disorder who underwent whole-exome sequencing; direct sequencing of the DCDC2 gene in 10 patients from 8 additional families did not identify any mutations.
Associations Pending Confirmation
For a discussion of a possible association between variation in the DCDC2 gene and dyslexia, see DYX2 (600202).
Meng et al. (2005) demonstrated that Dcdc2 RNA interference introduced into cells at the cerebral ventricular zone of rat embryos resulted in altered neuronal migration.
Schueler et al. (2015) found that Dcdc2-null mice developed periportal hepatic fibrosis with biliary duct proliferation at age 11 months. Knockdown of the dcdc2 gene in zebrafish embryos resulted in typical ciliopathy-related morphologic defects, including ventrally curved body axis, hydrocephalus, kidney cysts, kinky tails, and occasional pericardial edema. Laterality defects were also observed. Treatment with iCRT14, an inhibitor of the Wnt signaling pathway, rescued some of the defects, but high concentrations were toxic to embryos.
Grati et al. (2015) found that morpholino knockdown of dcdc2b in zebrafish resulted in high levels of hair cell abnormalities, such as body deformations, and often in the internalization of the stereocilia hair bundles and their respective kinocilia, reflecting early steps of hair cell degeneration. There was a reduction in the number of saccular hair cells as well as a reduction of hair cell response to stimuli. Morpholino morphants were not capable of swimming or hearing.
Nephronophthisis 19
In a patient, born of consanguineous parents, with nephronophthisis-19 (NPHP19; 616217), Schueler et al. (2015) identified a homozygous c.649A-T transversion (c.649A-T, NM_001195610.1) in exon 6 of the DCDC2 gene, resulting in a lys217-to-ter (K217X) substitution within the second doublecortin domain. The mutation was found by homozygosity mapping and whole-exome sequencing. In vitro cellular immunohistochemical studies showed that mutant DCDC2 failed to localize properly to primary cilia. The mutant protein was unable to rescue ciliopathy-related morphologic defects in dcdc2-null zebrafish, consistent with a loss of function.
Sclerosing Cholangitis, Neonatal
In a girl (patient 1), born of consanguineous parents of Asian descent, with neonatal sclerosing cholangitis (NSC; 617394), Grammatikopoulos et al. (2016) identified homozygosity for the K217X mutation in the DCDC2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Parental DNA was not available for segregation analysis. Patient liver samples showed absence of DCDC2 expression, consistent with a complete loss of function, as well as absence of normally constituted primary cilia in cholangiocytes.
Nephronophthisis 19
In a Czech patient with nephronophthisis-19 (NPHP19; 616217), Schueler et al. (2015) identified compound heterozygous mutations in the DCDC2 gene: a 2-bp deletion (c.123_124delGT, NM_001195610.1) in exon 2, resulting in a frameshift and premature termination (Ser42GlnfsTer72) within the first doublecortin domain, and an A-to-G transition in intron 3 (c.349-2A-G; 605755.0003), resulting in a splicing defect, a frameshift, and premature termination (Val117LeufsTer54). The patient was ascertained from a larger cohort of 800 families with NPHP-related ciliopathies who underwent direct sequencing of the DCDC2 gene. In vitro cellular immunohistochemical studies showed that mutant DCDC2 failed to localize properly to primary cilia. Expression of the deletion mutation was unable to rescue ciliopathy-related morphologic defects in dcdc2-null zebrafish, consistent with a loss of function.
Sclerosing Cholangitis, Neonatal
In an 18-year-old Caucasian man (patient 6), born of unrelated parents, with neonatal sclerosing cholangitis (NSC; 617394), Grammatikopoulos et al. (2016) identified homozygosity for the c.123_124delGT mutation in the DCDC2 gene. Another patient (patient 5) with NSC2 was compound heterozygous for the c.123_124delGT mutation and a nonsense mutation (L297X; 605755.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Parental DNA for patient 6 was not available for segregation analysis, but the unaffected parents of patient 5 were each heterozygous for 1 of the mutations. Patient liver samples showed absence of DCDC2 expression, consistent with a complete loss of function, as well as absence of normally constituted primary cilia in cholangiocytes.
For discussion of the c.349-2A-G mutation (c.349-2A-G, NM_001195610.1) in the DCDC2 gene that was found in compound heterozygous state in a patient with nephronophthisis-19 (NPHP19; 616217) by Schueler et al. (2015), see 605755.0002.
In affected members of a consanguineous Tunisian family with autosomal recessive deafness-66 (DFNB66; 610212), originally reported by Tlili et al. (2005), Grati et al. (2015) identified a homozygous c.1271A-C transversion (c.1271A-C, NM_001195610) in the DCDC2 gene, resulting in a gln424-to-pro (Q424P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 37), 1000 Genomes Project, or Exome Sequencing Project databases, or in 435 ancestry-matched controls. Overexpression of both wildtype and mutant DCDC2 in COS-7 cells disrupted the intracellular microtubule network by inducing the formation of extended cytosolic microtubule cables. In rat hair cells, Q424P caused a 2- to 3-fold increase in cilia length compared to wildtype, as well as other ciliary abnormalities, such as branching, duplication, and triplication, and stereocilia bundle degeneration.
In 2 brothers, born of consanguineous parents, with neonatal sclerosing cholangitis (NSC; 617394), Girard et al. (2016) identified a homozygous c.51G-C transversion (c.51G-C, NM_016356.3) in exon 1 of the DCDC2 gene, resulting in a lys17-to-asn (K17N) substitution at a highly conserved residue at the beginning of the first doublecortin domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database of 7,477 exomes. Patient cells showed loss of DCDC2 immunostaining in the ciliary axoneme of liver cholangiocytes and fewer cilia on cholangiocytes, as well as abnormal accumulation of the mutant protein in the cytoplasm compared to controls.
In 2 sibs, born of consanguineous parents, with neonatal sclerosing cholangitis (NSC; 617394), Girard et al. (2016) identified a homozygous 132-bp deletion (c.426_557del, NM_016356.3) in the DCDC2 gene, resulting in an in-frame deletion of 14 residues (Phe142_Arg186del) encompassing the entire exon 4 within the second doublecortin domain. The mutation, which was found by ciliary gene-targeting sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database of 7,477 exomes. PCR analysis of patient cells confirmed the deletion. Patient cells showed loss of DCDC2 immunostaining in the ciliary axoneme of liver cholangiocytes and fewer cilia on cholangiocytes, as well as abnormal accumulation of the mutant protein in the cytoplasm compared to controls.
In a 12-year-old girl of Greek descent (patient 2) neonatal sclerosing cholangitis (NSC; 617394), Grammatikopoulos et al. (2016) identified a homozygous c.890T-A transversion (c.890T-A, NM_001195610) in exon 7 of the DCDC2 gene, resulting in a leu297-to-ter (L297X) substitution. Three additional patients from 2 families were compound heterozygous for L297X and another pathogenic DCDC2 mutation: 1 Greek patient (patient 5) carried a 2-bp deletion (c.123_124delGT; 605755.0002) on the other allele, whereas 2 Greek sibs (patients 4 and 7) carried a 1-bp duplication in exon 4 (c.529dupA; 605755.0008), resulting in a frameshift and premature termination (Ile177AsnfsTer20), on the other allele. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Parental DNA was not available for segregation analysis for the sibs, but each unaffected parent of patient 5 was heterozygous for 1 of the mutations. Patient liver samples showed absence of DCDC2 expression, consistent with a complete loss of function, as well as absence of normally constituted primary cilia in cholangiocytes.
For discussion of the 1-bp duplication (c.529dupA, NM_001195610) in exon 4 of the DCDC2 gene, resulting in a frameshift and premature termination (Ile177AsnfsTer20), that was found in compound heterozygous state in 2 sibs with neonatal sclerosing cholangitis (NSC; 617394) by Grammatikopoulos et al. (2016), see 605755.0007.
In a 13-year-old African Caribbean girl from Saint Vincent and the Grenadines with nephronophthisis-19 (NPHP19; 616217), Slater et al. (2020) identified homozygosity for a c.383C-G transversion in exon 3 the DCDC2 gene, resulting in a ser128-to-ter (S128X) substitution. The mutation was identified by whole-exome sequencing. The DCDC2 gene was located in a 2.1-Mb area of homozygosity. In total, the patient was found to have 53 Mb of homozygosity, indicating identity by descent originating from a common ancestor between her parents. Functional studies were not performed. The patient also had psychiatric features, and the authors noted that the patient had variants of unknown significance in 5 other genes that were possibly related to the clinical phenotype.
Girard, M., Bizet, A. A., Lachaux, A., Gonzales, E., Filhol, E.,Collardeau-Frachon, S., Jeanpierre, C., Henry, C., Fabre, M., Viremouneix, L., Galmiche, L., Debray, D., and 10 others. DCDC2 mutations cause neonatal sclerosing cholangitis. Hum. Mutat. 37: 1025-1029, 2016. [PubMed: 27319779] [Full Text: https://doi.org/10.1002/humu.23031]
Grammatikopoulos, T., Sambrotta, M., Strautnieks, S., Foskett, P., Knisely, A. S., Wagner, B., Deheragoda, M., Starling, C., Mieli-Vergani, G., Smith, J., University of Washington Center for Mendelian Genomics, Bull, L., Thompson, R. J. Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis. J. Hepatol. 65: 1179-1187, 2016. [PubMed: 27469900] [Full Text: https://doi.org/10.1016/j.jhep.2016.07.017]
Grati, M., Chakchouk, I., Ma, Q., Bensaid, M., Desmidt, A., Turki, N., Yan, D., Baanannou, A., Mittal, R., Driss, N., Blanton, S., Farooq, A., Lu, Z., Liu, X. Z., Masmoudi, S. A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation. Hum. Molec. Genet. 24: 2482-2491, 2015. [PubMed: 25601850] [Full Text: https://doi.org/10.1093/hmg/ddv009]
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]
Meng, H., Powers, N. R., Tang, L., Cope, N. A., Zhang, P.-X., Fuleihan, R., Gibson, C., Page, G. P., Gruen, J. R. A dyslexia-associated variant in DCDC2 changes gene expression. Behav. Genet. 41: 58-66, 2011. [PubMed: 21042874] [Full Text: https://doi.org/10.1007/s10519-010-9408-3]
Meng, H., Smith, S. D., Hager, K., Held, M., Liu, J., Olson, R. K., Pennington, B. F., DeFries, J. C., Gelernter, J., O'Reilly-Pol, T., Somlo, S., Skudlarski, P., Shaywitz, S. E., Shaywitz, B. A., Marchione, K., Wang, Y., Paramasivam, M., LoTurco, J. J., Page, G. P., Gruen, J. R. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc. Nat. Acad. Sci. 102: 17053-17058, 2005. Note: Erratum: Proc. Nat. Acad. Sci. 102: 18763 only, 2005. [PubMed: 16278297] [Full Text: https://doi.org/10.1073/pnas.0508591102]
Schueler, M., Braun, D. A., Chandrasekar, G., Gee, H. Y., Klasson, T. D., Halbritter, J., Bieder, A., Porath, J. D., Airik, R., Zhou, W., LoTurco, J. J., Che, A., and 17 others. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. Am. J. Hum. Genet. 96: 81-92, 2015. [PubMed: 25557784] [Full Text: https://doi.org/10.1016/j.ajhg.2014.12.002]
Schumacher, J., Anthoni, H., Dahdouh, F., Konig, I. R., Hillmer, A. M., Kluck, N., Manthey, M., Plume, E., Warnke, A., Remschmidt, H., Hulsmann, J., Cichon, S., Lindgren, C. M., Propping, P., Zucchelli, M., Ziegler, A., Peyrard-Janvid, M., Schulte-Korne, G., Nothen, M. M., Kere, J. Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. Am. J. Hum. Genet. 78: 52-62, 2006. [PubMed: 16385449] [Full Text: https://doi.org/10.1086/498992]
Slater, B., Bekheirnia, N., Angelo, J., Bi, W., Braun, M. C., Bekheirnia, M. R. Nephronophthisis due to a novel DCDC2 variant in a patient from African-Caribbean descent: a case report. Am. J. Med. Genet. 182A: 527-531, 2020. [PubMed: 31821705] [Full Text: https://doi.org/10.1002/ajmg.a.61440]
Tlili, A., Mannikko, M., Charfedine, I., Lahmar, I., Benzina, Z., Ben Amor, M., Driss, N., Ala-Kokko, L., Drira, M., Masmoudi, S., Ayadi, H. A novel autosomal recessive non-syndromic deafness locus, DFNB66, maps to chromosome 6p21.2-22.3 in a large Tunisian consanguineous family. Hum. Hered. 60: 123-128, 2005. [PubMed: 16244493] [Full Text: https://doi.org/10.1159/000088974]
van den Eynde, B. J., Gaugler, B., Probst-Kepper, M., Michaux, L., Devuyst, O., Lorge, F., Weynants, P., Boon, T. A new antigen recognized by cytolytic T lymphocytes on a human kidney tumor results from reverse strand transcription. J. Exp. Med. 190: 1793-1799, 1999. [PubMed: 10601354] [Full Text: https://doi.org/10.1084/jem.190.12.1793]