Minibrain/DYRK1A-Gen: Kandidatengen für die mentale Retardierung bei Down-Syndrom?

Zusammenfassung:

DYRK1A ist das erste Mitglied einer jüngst beschriebenen Familie von Proteinkinasen mit dualer Spezifität. Das humane Gen für DYRK1A ist in einer für das Down-Syndrom kritischen Region des Chromosoms 21 (21q22.2) lokalisiert. durch seine Verwandtschaft zu dem Drosophila-Gen minibrain (Mnb), dessen Mutation zu spezifischen Defekten der Neurogenese führt, und aufgrund funktioneller Untersuchungen transgener Mäuse wird DYRK1A als Kandidatengen für die mentale Retardierung des Down-Syndroms diskutiert. Charakteristisch für die Kinase ist ihre Fähigkeit der Autophosphorylierung an Tyrosinresten und der Substratphosphorylierung an Serin-/Threoninresten. Ihre exakte zelluläre Funktion ist bisher nicht bekannt. Man weiß jedoch, dass DYRK1A in den Zellkern transportiert wird und nimmt an, dass sie Einfluss auf den Zellzyklus und damit auf das Wachstum und die Differenzierung von Geweben besitzt. Ihre pathogenetische Bedeutung für das Down-Syndrom bedarf weiterer Klärung.

DYRK1A is the first member of a novel subfamily of protein kinases with dual specificity. The human gene for DYRK1A is located in the “Down syndrome critical region” (21q22.2). Due to its relationship to the Drosophila gene minibrain (Mnb), whose mutation results in specific defects in neurogenesis, and based on functional experiments on transgenic mice, DYRK1A is discussed as a candidate gene for mental retardation in Down syndrome. The kinase is characterized by its ability to catalyze tyrosine-directed autophosphorylation as well as phosphorylation of serine/threonine residues in substrates. Its exact cellular function is yet unknown. DYRK1A is, however, known to be translocated into the nucleus and supposed to be involved in the control of cell growth and development. The pathogenetic impact of DYRK1A on Down syndrome needs further elucidation.

Schlüsselwörter:

Down-Syndrom - Trisomie 21 - DYRK1A - Minibrain

Key words:

Down Syndrome - Trisomy 21 - DYRK1A - Minibrain

Literatur

• 01 Becker  W, Joost  H G. Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity.  Prog Nucleic Acid Res Mol Biol. 1999;  62 1-17
• 02 Becker  W, Weber  Y, Wetzel  K, Eirmbter  K, Tejedor  F J, Joost  G. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel famila of dual specificity protein kinases.  J Biol Chem. 1998;  273 25893-25902
• 03 Chen  H, Antonarakis  S E. Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2.  Hum Genet. 1997;  99 (2) 262-265
• 04 Delabar  J M, Sinet  P M, Chadefaux  B, Nicole  A, Gegonne  A, Stehelin  D, Fridlansky  F, Creau-Goldberg  N, Turleau  C, de Grouchy  J. Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype (Down syndrome).  Hum Genet. 1987;  76 (3) 225-229
• 05 Fischbach  K-F, Heisenberg  M. Neurogenetics and behavior in insects.  J Exp Biol. 1984;  112 65-93
• 06 Garrett  S, Menold  M M, Broach  J R. The Saccharomyces cerevisiae YAK1 gene encodes a protein kinase that is induced by arrest early in the cell cycle.  Mol Cell Biol. 1991;  11 (8) 4045-4052
• 07 Guimera  J, Casas  C, Pucharcos  C, Solans  A, Domenech  A, Planas  A M, Ashley  J, Lovett  M, Estivill  X, Pritchard  M A. A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region.  Hum Mol Genet. 1996;  5 (9) 1305-1310
• 08 Hanks  S K, Hunter  T. Protein kinase 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification.  Faseb J. 1995;  9 (8) 576-596
• 09 Hanks  S K, Quinn  A M. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members.  Methods Enzymol. 1991;  200 38-62
• 10 Kentrup  H, Becker  W, Heukelbach  J, Wilmes  A, Schurmann  A, Huppertz  C, Kainulainen  H, Joost  H G. Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII.  J Biol Chem . 1996;  271 (7) 3488-3495
• 11 Leder  S, Weber  Y, Altafaj  X, Estivill  X, Joost  H G, Becker  W. Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases.  Biochem Biophys Res Commun. 1999;  254 (2) 474-479
• 12 McCormick  M K, Schinzel  A, Petersen  M B, Stetten  G, Driscoll  D J, Cantu  E S, Tranebjaerg  L, Mikkelsen  M, Watkins  P C, Antonarakis  S E. Molecular genetic approach to the characterization of the „Down syndrome region” of chromosome 21.  Genomics. 1989;  5 (2) 325-331
• 13 Pennisi  E. Genes, junctions, and disease at cell biology meeting (news).  Science. 1996;  274 (5295) 2008-2009
• 14 Rahmani  Z, Blouin  J L, Creau-Goldberg  N, Watkins  P C, Mattei  J F, Poissonnier  M, Prieur  M, Chettouh  Z, Nicole  A, Aurias  A et al. Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome.  Proc Natl Acad Sci USA. 1989;  86 (15) 5958-5962
• 15 Rogers  S, Wells  R, Rechsteiner  M. Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis.  Science. 1986;  234 (4774) 364-368
• 16 Shindoh  N, Kudoh  J, Maeda  H, Yamaki  A, Minoshima  S, Shimizu  Y, Shimizu  N. Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from „the Down syndrome critical region” of chromosome 21.  Biochim Biophys Res Commun. 1996;  225 (1) 92-99
• 17 Sinet  P M, Theophile  D, Rahmani  Z, Chettouh  Z, Blouin  J L, Prieur  M, Noel  B, Delabar  J M. Mapping of the Down syndrome phenotype on chromosome 21 at the molecular level.  Biomed Pharmacother. 1994;  48 (5 - 6) 247-252
• 18 Smith  D J, Stevens  M E, Sudanagunta  S P, Bronson  R T, Makhinson  M, Watabe  A M, TJ  O D, Fung  J, Weier  H U, Cheng  J F, Rubin  E M. Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome.  Nat Genet. 1997;  16 (1) 28-36
• 19 Song  W J, Chung  S H, Kurnit  D M. The murine Dyrk protein maps to chromosome 16, localizes to the nucleus, and can form multimers.  Biochem Biophys Res Commun. 1997;  231 (3) 640-644
• 20 Song  W J, Sternberg  L R, Kasten Sportes  C, Keuren  M L, Chung  S H, Slack  A C, Miller  D E, Glover  T W, Chiang  P W, Lou  L, Kurnit  D M. Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome „critical region”.  Genomics. 1996;  38 (3) 331-339
• 21 Tejedor  F, Zhu  X R, Kaltenbach  E, Ackermann  A, Baumann  A, Canal  I, Heisenberg  M, Fischbach  K F, Pongs  O. Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila.  Neuron. 1995;  14 (2) 287-301