| Structural highlights
Disease
DCX_HUMAN Defects in DCX are the cause of lissencephaly X-linked type 1 (LISX1) [MIM:300067; also called X-LIS or LIS. LISX1 is a classic lissencephaly characterized by mental retardation and seizures that are more severe in male patients. Affected boys show an abnormally thick cortex with absent or severely reduced gyri. Clinical manifestations include feeding problems, abnormal muscular tone, seizures and severe to profound psychomotor retardation. Female patients display a less severe phenotype referred to as 'doublecortex'.[1] [2] [3] [4] [5] [6] Defects in DCX are the cause of subcortical band heterotopia X-linked (SBHX) [MIM:300067; also known as double cortex or subcortical laminar heterotopia (SCLH). SBHX is a mild brain malformation of the lissencephaly spectrum. It is characterized by bilateral and symmetric plates or bands of gray matter found in the central white matter between the cortex and cerebral ventricles, cerebral convolutions usually appearing normal.[7] [8] [9] [10] [11] [12] [13] [14] Note=A chromosomal aberration involving DCX is found in lissencephaly. Translocation t(X;2)(q22.3;p25.1).
Function
DCX_HUMAN Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development. May act by competing with the putative neuronal protein kinase DCLK1 in binding to a target protein. May in that way participate in a signaling pathway that is crucial for neuronal interaction before and during migration, possibly as part of a calcium ion-dependent signal transduction pathway. May be part with PAFAH1B1/LIS-1 of overlapping, but distinct, signaling pathways that promote neuronal migration.[15]
Publication Abstract from PubMed
Doublecortin is a microtubule-associated protein produced during neurogenesis. The protein stabilizes microtubules and stimulates their polymerization which allows migration of immature neurons to their designated location in the brain. Mutations in the gene that impair doublecortin function and cause severe brain formation disorders are located on a tandem repeat of two doublecortin domains. The molecular mechanism of action of doublecortin is only incompletely understood. Anti-doublecortin antibodies such as the rabbit polyclonal Abcam 18732 are widely used as neurogenesis markers. Here, we report the generation and characterization of antibodies that bind to single doublecortin domains. The antibodies were used as tools to obtain structures of both domains. Four independent crystal structures of the N-terminal domain reveal several distinct open and closed conformations of the peptide linking N- and C-terminal domains which can be related to doublecortin function. An NMR assignment and a crystal structure in complex with a camelid antibody fragment show that the doublecortin C-terminal domain adopts the same well defined ubiquitin like fold as the N-terminal domain, despite its reported aggregation and molten globule like properties. The antibodies' unique domain specificity also renders them ideal research tools to better understand the role of individual domains in doublecortin function. A single chain camelid antibody fragment specific for the C-terminal doublecortin domain affected microtubule binding whereas a monoclonal mouse antibody specific for the N-terminal domain did not. Together with steric considerations this suggests the microtubule interacting doublecortin domain observed in cryo-electron micrographs to be the C-terminal domain rather than the N-terminal.
Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies.,Burger D, Stihle M, Sharma A, Di Lello P, Benz J, D'Arcy B, Debulpaep M, Fry D, Huber W, Kremer T, Laeremans T, Matile H, Ross A, Rufer AC, Schoch G, Steinmetz MO, Steyaert J, Rudolph MG, Thoma R, Ruf A J Biol Chem. 2016 May 10. pii: jbc.M116.726547. PMID:27226599[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ des Portes V, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrie A, Gelot A, Dupuis E, Motte J, Berwald-Netter Y, Catala M, Kahn A, Beldjord C, Chelly J. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell. 1998 Jan 9;92(1):51-61. PMID:9489699
- ↑ Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell. 1998 Jan 9;92(1):63-72. PMID:9489700
- ↑ Sossey-Alaoui K, Hartung AJ, Guerrini R, Manchester DK, Posar A, Puche-Mira A, Andermann E, Dobyns WB, Srivastava AK. Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects. Hum Mol Genet. 1998 Aug;7(8):1327-32. PMID:9668176
- ↑ Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, Walsh CA, Barkovich AJ, Dobyns WB, Ledbetter DH, Ross ME. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet. 1998 Dec;7(13):2029-37. PMID:9817918
- ↑ Demelas L, Serra G, Conti M, Achene A, Mastropaolo C, Matsumoto N, Dudlicek LL, Mills PL, Dobyns WB, Ledbetter DH, Das S. Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology. 2001 Jul 24;57(2):327-30. PMID:11468322
- ↑ Aigner L, Uyanik G, Couillard-Despres S, Ploetz S, Wolff G, Morris-Rosendahl D, Martin P, Eckel U, Spranger S, Otte J, Woerle H, Holthausen H, Apheshiotis N, Fluegel D, Winkler J. Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders. Neurology. 2003 Jan 28;60(2):329-32. PMID:12552055
- ↑ des Portes V, Francis F, Pinard JM, Desguerre I, Moutard ML, Snoeck I, Meiners LC, Capron F, Cusmai R, Ricci S, Motte J, Echenne B, Ponsot G, Dulac O, Chelly J, Beldjord C. doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet. 1998 Jul;7(7):1063-70. PMID:9618162
- ↑ Gleeson JG, Minnerath SR, Fox JW, Allen KM, Luo RF, Hong SE, Berg MJ, Kuzniecky R, Reitnauer PJ, Borgatti R, Mira AP, Guerrini R, Holmes GL, Rooney CM, Berkovic S, Scheffer I, Cooper EC, Ricci S, Cusmai R, Crawford TO, Leroy R, Andermann E, Wheless JW, Dobyns WB, Walsh CA, et al.. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann Neurol. 1999 Feb;45(2):146-53. PMID:9989615
- ↑ Kato M, Kimura T, Lin C, Ito A, Kodama S, Morikawa T, Soga T, Hayasaka K. A novel mutation of the doublecortin gene in Japanese patients with X-linked lissencephaly and subcortical band heterotopia. Hum Genet. 1999 Apr;104(4):341-4. PMID:10369164
- ↑ Pilz DT, Kuc J, Matsumoto N, Bodurtha J, Bernadi B, Tassinari CA, Dobyns WB, Ledbetter DH. Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. Hum Mol Genet. 1999 Sep;8(9):1757-60. PMID:10441340
- ↑ Sakamoto M, Ono J, Okada S, Nakamura Y, Kurahashi H. Genetic alteration of the DCX gene in Japanese patients with subcortical laminar heterotopia or isolated lissencephaly sequence. J Hum Genet. 2000;45(3):167-70. PMID:10807542 doi:10.1007/s100380050204
- ↑ Kato M, Kanai M, Soma O, Takusa Y, Kimura T, Numakura C, Matsuki T, Nakamura S, Hayasaka K. Mutation of the doublecortin gene in male patients with double cortex syndrome: somatic mosaicism detected by hair root analysis. Ann Neurol. 2001 Oct;50(4):547-51. PMID:11601509
- ↑ Matsumoto N, Leventer RJ, Kuc JA, Mewborn SK, Dudlicek LL, Ramocki MB, Pilz DT, Mills PL, Das S, Ross ME, Ledbetter DH, Dobyns WB. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet. 2001 Jan;9(1):5-12. PMID:11175293 doi:10.1038/sj.ejhg.5200548
- ↑ D'Agostino MD, Bernasconi A, Das S, Bastos A, Valerio RM, Palmini A, Costa da Costa J, Scheffer IE, Berkovic S, Guerrini R, Dravet C, Ono J, Gigli G, Federico A, Booth F, Bernardi B, Volpi L, Tassinari CA, Guggenheim MA, Ledbetter DH, Gleeson JG, Lopes-Cendes I, Vossler DG, Malaspina E, Franzoni E, Sartori RJ, Mitchell MH, Mercho S, Dubeau F, Andermann F, Dobyns WB, Andermann E. Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females. Brain. 2002 Nov;125(Pt 11):2507-22. PMID:12390976
- ↑ Slepak TI, Salay LD, Lemmon VP, Bixby JL. Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskeleton (Hoboken). 2012 Jul;69(7):514-27. doi: 10.1002/cm.21021. Epub 2012, Mar 7. PMID:22359282 doi:10.1002/cm.21021
- ↑ Burger D, Stihle M, Sharma A, Di Lello P, Benz J, D'Arcy B, Debulpaep M, Fry D, Huber W, Kremer T, Laeremans T, Matile H, Ross A, Rufer AC, Schoch G, Steinmetz MO, Steyaert J, Rudolph MG, Thoma R, Ruf A. Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies. J Biol Chem. 2016 May 10. pii: jbc.M116.726547. PMID:27226599 doi:http://dx.doi.org/10.1074/jbc.M116.726547
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