Alternative titles; symbols
HGNC Approved Gene Symbol: DOCK6
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:11,199,295-11,262,524 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Adams-Oliver syndrome 2 | 614219 | Autosomal recessive | 3 |
DOCK6 is a member of the conserved DOCK family of atypical guanine nucleotide exchange factors (GEFs) that lack a catalytic DBL (MCF2; 311030) homology domain. DOCK6 belongs to subfamily C of the DOCK family and has a role in remodeling the actin cytoskeleton by functioning as a GEF for both CDC42 (116952) and RAC1 (602048) Miyamoto et al. (2007).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2000) cloned DOCK6, which they designated KIAA1395. The deduced protein contains 1,628 amino acids. RT-PCR ELISA detected variable DOCK6 expression in all adult and fetal tissues and adult brain regions examined, with highest expression in ovary, lung, heart, and kidney, and lowest expression in spleen.
By searching a database for sequences similar to DOCK180 (DOCK1; 601403), Cote and Vuori (2002) identified DOCK6. The deduced protein contains an N-terminal domain of over 200 amino acids and a C-terminal domain of over 500 amino acids that share significant similarity with other DOCK proteins. Cote and Vuori (2002) called these regions DOCK homology region-1 (DHR1) and DHR2, respectively. DHR2 was predicted to function in guanine nucleotide exchange.
Miyamoto et al. (2007) found that transfected COS-7 cells expressed epitope-tagged human DOCK6 DHR2 near the cell surface and in the perinuclear region. Western blot analysis of mouse N1E-115 neuroblastoma cells showed that full-length mouse Dock6 had an apparent molecular mass of 200 kD.
By quantitative RT-PCR of adult mouse tissues, Shaheen et al. (2011) detected highest Dock6 expression in lung and heart, with lower expression in brain, cerebellum, eye, kidney, liver, and spleen. In situ hybridization of mouse embryos showed that Dock6 was expressed in the growing edge of limb buds and in heart at embryonic day 9.5. By embryonic day 13.5, Dock6 expression was more concentrated in developing digits.
Shaheen et al. (2011) determined that the DOCK6 gene contains 48 exons.
By radiation hybrid analysis, Nagase et al. (2000) mapped the DOCK6 gene to chromosome 19. Hartz (2011) mapped the DOCK6 gene to chromosome 19p13.2 based on an alignment of the DOCK6 sequence (GenBank AB037816) with the genomic sequence (GRCh37).
Using full-length human DOCK6 or the isolated DHR2 of DOCK6 expressed in E. coli, Miyamoto et al. (2007) showed that DOCK6 functioned as a GEF for RAC1 and CDC42, but not for RHOA (165390). Similar to other DOCK proteins, the isolated DHR2 of DOCK6 showed higher activity than full-length DOCK6. Transfection of COS-7 cells with human DOCK6 DHR2 increased the number of cells displaying both lamellipodia and filopodia, which are markers of Rac1 and Cdc42 activation, respectively. Dock6 mRNA and protein were induced upon differentiation in mouse N1E-115 neuroblastoma cells, concomitant with increased levels of GTP-bound Rac1 and Cdc42. Overexpression of human DOCK6 DHR2 promoted neurite outgrowth in N1E-115 cells. Conversely, knockdown of endogenous Dock6 in N1E-115 cells inhibited neurite outgrowth after induction of differentiation. Miyamoto et al. (2007) concluded that DOCK6 functions as a GEF for RAC1 and CDC42 and has a role in cytoskeletal remodeling and neurite outgrowth.
In 2 unrelated Arab girls with autosomal recessive Adams-Oliver syndrome-2 (AOS2; 614219), Shaheen et al. (2011) identified homozygosity for 2 different truncating mutations in the DOCK6 gene (614194.0001 and 614194.0002, respectively) that segregated with disease in each family.
In affected individuals from 2 consanguineous Arab families with AOS who shared a region of homozygosity overlapping the DOCK6 gene, Shaheen et al. (2013) identified homozygous mutations in DOCK6 (614914.0003 and 614914.0004, respectively).
In a 6-year-old girl with severely impaired intellectual development, microcephaly, and esotropia, who was born to consanguineous Iranian parents, Zaersabet et al. (2023) identified homozygosity for a splice site mutation in a conserved sequence in exon 11 of the DOCK6 gene (c.1258+2T-G, NM_020812.4), predicted to result in abnormal splicing. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. It was classified as likely pathogenic by ACMG criteria. The variant was not present in population databases, including 1000 Genomes Project and ExAC. The findings in the patient were consistent with Adams-Oliver syndrome, but she did not have aplasia cutis congenita of the scalp or terminal transverse limb defects.
In an 11-month-old Arab girl with Adams-Oliver syndrome-2 (AOS2; 614219), born of double first-cousin parents, Shaheen et al. (2011) identified homozygosity for a 4-bp deletion (1362delAACT) in the DOCK6 gene, predicted to result in a mutant protein lacking the 2 fundamental domains, DHR1 and DHR2. Her unaffected parents were heterozygous for the mutation. Examination of cytoskeletal organization in patient fibroblasts showed that approximately 16% of cells assumed a rounded phenotype that was not observed in control cells; patient cells also assumed an unusual elongated morphology and lacked lamellipodia and lateral ruffles.
In a 3.5-year-old Arab girl with Adams-Oliver syndrome-2 (AOS2; 614219), born of unaffected first-cousin parents, Shaheen et al. (2011) identified homozygosity for a 1-bp duplication (1245dupT) in the DOCK6 gene, predicted to result in a mutant protein lacking the 2 fundamental domains, DHR1 and DHR2. The mutation segregated with disease in the family.
In a 12-month old Arab boy with Adams-Oliver syndrome (AOS2; 614219), who was born of first-cousin parents, Shaheen et al. (2013) identified homozygosity for a 1-bp duplication (c.2520dupT) in the DOCK6 gene, resulting in a frameshift and introduction of a premature termination codon (Arg841SerfsTer6). The patient's affected sister exhibited gastroschisis in addition to other features of AOS.
In a female patient (patient 10.1) with AOS who was born of consanguineous parents, Sukalo et al. (2015) identified homozygosity for the c.2520dupT mutation (c.2520dupT, NM_020812.3) in exon 21 of the DOCK6 gene. In addition to the typical AOS features of scalp defect and terminal transverse limb defects, the patient exhibited microcephaly with seizures and multiple brain anomalies, including ventricular dilation with mild brain atrophy, corpus callosum hypoplasia, and periventricular calcifications.
In a 2-year-old girl Arab girl with Adams-Oliver syndrome (AOS2; 614219), born of first-cousin parents, Shaheen et al. (2013) identified homozygosity for a c.4107-1G-C transversion at the splice acceptor site in intron 32 of the DOCK6 gene. RT-PCR confirmed that the mutation replaces the consensus acceptor site by a cryptic site in the downstream exon (exon 33), leading to the loss of 7 bp from exon 33 and causing a frameshift that results in a premature termination codon (Thr1370MetfsTer19).
In a sister and brother (family 6) with Adams-Oliver syndrome-2 (AOS2; 614219), originally described by Orstavik et al. (1995), Sukalo et al. (2015) identified compound heterozygosity for 2 mutations in the DOCK6 gene: a c.788T-A transversion (c.788T-A, NM_020812.3) in exon 7, resulting in a val263-to-asp (V263D) substitution at a conserved residue within the DHR-1 domain, and a splice site mutation (c.5939+2T-C; 614194.0006) in intron 46. The missense mutation was inherited from their unaffected father, and the splice site mutation from their unaffected mother.
For discussion of the c.5939+2T-C transition (rs201387914) in intron 46 of the DOCK6 gene that was found in compound heterozygous state in a sister and brother with Adam-Oliver syndrome-2 (AOS2; 614219) by Sukalo et al. (2015), see 614194.0005.
In a 9-year-old Afghan boy (patient 5.1) with Adams-Oliver syndrome-2 (AOS2; 614219), originally reported by Prothero et al. (2007), Sukalo et al. (2015) identified homozygosity for a c.3154G-A transition (c.3154G-A, NM_020812.3) in exon 26 of the DOCK6 gene, resulting in a glu1052-to-lys (E1052K) substitution at a conserved residue in the DHR-1 domain.
Cote, J.-F., Vuori, K. Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. J. Cell Sci. 115: 4901-4913, 2002. [PubMed: 12432077] [Full Text: https://doi.org/10.1242/jcs.00219]
Hartz, P. A. Personal Communication. Baltimore, Md. 8/30/2011.
Miyamoto, Y., Yamauchi, J., Sanbe, A., Tanoue, A. Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth. Exp. Cell Res. 313: 791-804, 2007. [PubMed: 17196961] [Full Text: https://doi.org/10.1016/j.yexcr.2006.11.017]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Orstavik, K. H., Stromme, P., Spetalen, S., Flage, T., Westvik, J., Vesterhus, P., Skjeldal, O. Aplasia cutis congenita associated with limb, eye, and brain anomalies in sibs: a variant of the Adams-Oliver syndrome? Am. J. Med. Genet. 59: 92-95, 1995. [PubMed: 8849019] [Full Text: https://doi.org/10.1002/ajmg.1320590118]
Prothero, J., Nicholl, R., Wilson, J., Wakeling, E. L. Aplasia cutis congenita, terminal limb defects and falciform retinal folds: confirmation of a distinct syndrome of vascular disruption. Clin. Dysmorph. 16: 39-41, 2007. [PubMed: 17159513] [Full Text: https://doi.org/10.1097/MCD.0b013e328010b81c]
Shaheen, R., Aglan, M., Keppler-Noreuil, K., Faqeih, E., Ansari, S., Horton, K., Ashour, A., Zaki, M. S., Al-Zahrani, F., Cueto-Gonalez, A. M., Abdel-Salam, G., Temtamy, S., Alkuraya, F. S. Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams Oliver syndrome. Am. J. Hum. Genet. 92: 598-604, 2013. [PubMed: 23522784] [Full Text: https://doi.org/10.1016/j.ajhg.2013.02.012]
Shaheen, R., Faqeih, E., Sunker, A., Morsy, H., Al-Sheddi, T., Shamseldin, H. E., Adly, N., Hashem, M., Alkuraya, F. S. Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. Am. J. Hum. Genet. 89: 328-333, 2011. [PubMed: 21820096] [Full Text: https://doi.org/10.1016/j.ajhg.2011.07.009]
Sukalo, M., Tilsen, F., Kayserili, H., Muller, D., Tuysuz, B., Ruddy, D. M., Wakeling, E., Orstavik, K. H., Bramswig, N. C., Snape, K. M., Trembath, R., De Smedt, M., van der Aa, N., Skalej, M., Mundlos, S., Wuyts, W., Southgate, L., Zenker, M. DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies. Hum. Mutat. 36: 593-598, 2015. Note: Erratum: Hum. Mutat. 36: 1112 only, 2015. [PubMed: 25824905] [Full Text: https://doi.org/10.1002/humu.22795]
Zaersabet, M., Koochakkhani, S., Sarmast, Y., Salmani, H. Homozygosity for a novel DOCK6 variant in an individual without aplasia cutis congenita of the scalp and terminal transverse limb defects. Clin. Dysmorph. 32: 84-87, 2023. [PubMed: 36779775] [Full Text: https://doi.org/10.1097/MCD.0000000000000450]