Transcriptional dysregulation and impairment of PHOX2B auto-regulatory mechanism induced by polyalanine expansion mutations associated with congenital central hypoventilation syndrome

Neurobiology of Disease

Volumn 50, Issue 1, 2013, Pages 187-200

  Di Lascio, Simona ^a   Bachetti, Tiziana ^c   Saba, Elena ^b   Ceccherini, Isabella ^c   Benfante, Roberta ^a,b   Fornasari, Diego ^a,b  

^a UNIVERSITY OF MILAN   (Italy)

^b CNR   (Italy)

^c G GASLINI INSTITUTE   (Italy)

Author keywords

Congenital central hypoventilation syndrome; DNA binding; Dominant negative; PHOX2B; Polyalanine mutations

Indexed keywords

ALANINE; PAIRED LIKE HOMEOBOX 2B PROTEIN; TRANSCRIPTION FACTOR; UNCLASSIFIED DRUG;

ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL NUCLEUS; CONGENITAL CENTRAL HYPOVENTILATION SYNDROME; CONTROLLED STUDY; CYTOPLASM; DBH GENE; DNA BINDING; DNA STRUCTURE; GENE; GENE DELETION; GENE MUTATION; GENETIC ASSOCIATION; HETEROZYGOSITY; IN VITRO STUDY; MUTANT; PATHOGENESIS; PHOX2A GENE; PHOX2B GENE; POLYALANINE EXPANSION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN LOCALIZATION; TLX2 GENE; TRANSACTIVATION; TRANSCRIPTION REGULATION; WILD TYPE;

BLOTTING, WESTERN; DNA REPEAT EXPANSION; ELECTROPHORETIC MOBILITY SHIFT ASSAY; FLUORESCENT ANTIBODY TECHNIQUE; HELA CELLS; HOMEODOMAIN PROTEINS; HUMANS; HYPOVENTILATION; MUTATION; PEPTIDES; PROMOTER REGIONS, GENETIC; SLEEP APNEA, CENTRAL; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC; TRANSCRIPTIONAL ACTIVATION; TRANSFECTION;

EID: 84869018090     PISSN: 09699961     EISSN: 1095953X     Source Type: Journal    
DOI: 10.1016/j.nbd.2012.10.019     Document Type: Article

References (43)

1. Adachi M., Browne D., Lewis E.J. Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription. DNA Cell Biol. 2000, 19:539-554.
2. Albrecht A., Mundlos S. The other trinucleotide repeat: polyalanine expansion disorders. Curr. Opin. Genet. Dev. 2005, 15:285-293.
3. Albrecht A.N., Kornak U., Boddrich A., Suring K., Robinson P.N., Stiege A.C., et al. A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. Hum. Mol. Genet. 2004, 13:2351-2359.
4. Amiel J., Laudier B., Attie-Bitach T., Trang H., de Pontual L., Gener B., et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat. Genet. 2003, 33:459-461.
5. Amiel J., Trochet D., Clement-Ziza M., Munnich A., Lyonnet S. Polyalanine expansions in human. Hum. Mol. Genet. 2004, 13(Spec No 2):R235-R243.
6. Bachetti T., Matera I., Borghini S., Di Duca M., Ravazzolo R., Ceccherini I. Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. Hum. Mol. Genet. 2005, 14:1815-1824.
7. Bachetti T., Bocca P., Borghini S., Matera I., Prigione I., Ravazzolo R., et al. Geldanamycin promotes nuclear localisation and clearance of PHOX2B misfolded proteins containing polyalanine expansions. Int. J. Biochem. Cell Biol. 2007, 39:327-339.
8. Battaglioli E., Gotti C., Terzano S., Flora A., Clementi F., Fornasari D. Expression and transcriptional regulation of the human alpha3 neuronal nicotinic receptor subunit in T lymphocyte cell lines. J. Neurochem. 1998, 71:1261-1270.
9. Benfante R., Flora A., Di Lascio S., Cargnin F., Longhi R., Colombo S., et al. Transcription factor PHOX2A regulates the human alpha3 nicotinic receptor subunit gene promoter. J. Biol. Chem. 2007, 282:13290-13302.
10. Borghini S., Bachetti T., Fava M., Di Duca M., Cargnin F., Fornasari D., et al. The TLX2 homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells. Biochem. J. 2006, 395:355-361.
11. Brown L.Y., Brown S.A. Alanine tracts: the expanding story of human illness and trinucleotide repeats. Trends Genet. 2004, 20:51-58.
12. Bruneau S., Johnson K.R., Yamamoto M., Kuroiwa A., Duboule D. The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. Dev. Biol. 2001, 237:345-353.
13. Brunet J.F., Pattyn A. Phox2 genes - from patterning to connectivity. Curr. Opin. Genet. Dev. 2002, 12:435-440.
14. Cargnin F., Flora A., Di Lascio S., Battaglioli E., Longhi R., Clementi F., et al. PHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism. J. Biol. Chem. 2005, 280:37439-37448.
15. Coppola E., d'Autreaux F., Rijli F.M., Brunet J.F. Ongoing roles of Phox2 homeodomain transcription factors during neuronal differentiation. Development 2010, 137:4211-4220.
16. Davies J.E., Sarkar S., Rubinsztein D.C. Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation. Hum. Mol. Genet. 2008, 17:1097-1108.
17. Di Zanni E., Bachetti T., Parodi S., Bocca P., Prigione I., Di Lascio S., et al. In vitro drug treatments reduce the deleterious effects of aggregates containing polyAla expanded PHOX2B proteins. Neurobiol. Dis. 2012, 45:508-518.
18. Dubreuil V., Hirsch M.R., Jouve C., Brunet J.F., Goridis C. The role of Phox2b in synchronizing pan-neuronal and type-specific aspects of neurogenesis. Development 2002, 129:5241-5253.
19. Dubreuil V., Ramanantsoa N., Trochet D., Vaubourg V., Amiel J., Gallego J., et al. A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:1067-1072.
20. Durand E., Lofaso F., Dauger S., Vardon G., Gaultier C., Gallego J. Intermittent hypoxia induces transient arousal delay in newborn mice. J. Appl. Physiol. 2004, 96:1216-1222. (discussion 1196).
21. Flora A., Lucchetti H., Benfante R., Goridis C., Clementi F., Fornasari D. Sp proteins and Phox2b regulate the expression of the human Phox2a gene. J. Neurosci. 2001, 21:7037-7045.
22. Goridis C., Dubreuil V., Thoby-Brisson M., Fortin G., Brunet J.F. Phox2b, congenital central hypoventilation syndrome and the control of respiration. Semin. Cell Dev. Biol. 2010, 21:814-822.
23. Hong S.J., Kim C.H., Kim K.S. Structural and functional characterization of the 5' upstream promoter of the human Phox2a gene: possible direct transactivation by transcription factor Phox2b. J. Neurochem. 2001, 79:1225-1236.
24. Hung C.C., Su Y.N., Tsao P.N., Chen P.C., Lin S.J., Lin C.H., Mu S.C., Liu C.A., et al. Unequal crossover recombination - population screening for PHOX2B gene polyalanine polymorphism using CE. Electrophoresis 2007, 28:894-899.
25. Matera I., Bachetti T., Puppo F., Di Duca M., Morandi F., Casiraghi G.M., et al. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome. J. Med. Genet. 2004, 41:373-380.
26. Messaed C., Rouleau G.A. Molecular mechanisms underlying polyalanine diseases. Neurobiol. Dis. 2009, 34:397-405.
27. Nasrallah I.M., Minarcik J.C., Golden J.A. A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. J. Cell Biol. 2004, 167:411-416.
28. Parodi S., Di Zanni E., Di Lascio S., Bocca P., Prigione I., Fornasari D., et al. The E3 ubiquitin ligase TRIM11 mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expanded PHOX2B. J. Mol. Med. 2012, 90:1025-1035.
29. Pattyn A., Morin X., Cremer H., Goridis C., Brunet J.F. The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 1999, 399:366-370.
30. Reiff T., Tsarovina K., Majdazari A., Schmidt M., del Pino I., Rohrer H. Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. J. Neurosci. 2010, 30:905-915.
31. Rigamonti D., Bauer J.H., De-Fraja C., Conti L., Sipione S., Sciorati C., et al. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 2000, 20:3705-3713.
32. Seo H., Hong S.J., Guo S., Kim H.S., Kim C.H., Hwang D.Y., et al. A direct role of the homeodomain proteins Phox2a/2b in noradrenaline neurotransmitter identity determination. J. Neurochem. 2002, 80:905-916.
33. Terzano S., Flora A., Clementi F., Fornasari D. The minimal promoter of the human alpha 3 nicotinic receptor subunit gene. Molecular and functional characterization. J. Biol. Chem. 2000, 275:41495-41503.
34. Toyota T., Yoshitsugu K., Ebihara M., Yamada K., Ohba H., Fukasawa M., et al. Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum. Mol. Genet. 2004, 13:551-561.
35. Trochet D., Bourdeaut F., Janoueix-Lerosey I., Deville A., de Pontual L., Schleiermacher G., et al. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am. J. Hum. Genet. 2004, 74:761-764.
36. Trochet D., Hong S.J., Lim J.K., Brunet J.F., Munnich A., Kim K.S., et al. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum. Mol. Genet. 2005, 14:3697-3708.
37. Trochet D., de Pontual L., Estevao M.H., Mathieu Y., Munnich A., Feingold J., et al. Homozygous mutation of the PHOX2B gene in congenital central hypoventilation syndrome (Ondine's Curse). Hum. Mutat. 2008, 29:770.
38. Trochet D., Mathieu Y., Pontual L., Savarirayan R., Munnich A., Brunet J.F., et al. In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation. Hum. Mutat. 2009, 30:E421-E431.
39. Weese-Mayer D.E., Berry-Kravis E.M., Zhou L., Maher B.S., Silvestri J.M., Curran M.E., et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am. J. Med. Genet. A 2003, 123A:267-278.
40. Weese-Mayer D.E., Rand C.M., Berry-Kravis E.M., Jennings L.J., Loghmanee D.A., Patwari P.P., et al. Congenital central hypoventilation syndrome from past to future: model for translational and transitional autonomic medicine. Pediatr. Pulmonol. 2009, 44:521-535.
41. Wu H.T., Su Y.N., Hung C.C., Hsieh W.S., Wu K.J. Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants. Hum. Mutat. 2009, 30:655-660.
42. Yang C., Kim H.S., Seo H., Kim K.S. Identification and characterization of potential cis-regulatory elements governing transcriptional activation of the rat tyrosine hydroxylase gene. J. Neurochem. 1998, 71:1358-1368.
43. Zoghbi H.Y., Orr H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 2000, 23:217-247.