Nonsense mutations of the bHLH transcription factor TWIST2 found in Setleis Syndrome patients cause dysregulation of periostin.
Enviado por Carmen Lydia Cadilla el
Título | Nonsense mutations of the bHLH transcription factor TWIST2 found in Setleis Syndrome patients cause dysregulation of periostin. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Autores | Franco, HL, Casasnovas, JJ, Leon, RG, Friesel, R, Ge, Y, Desnick, RJ, Cadilla, C |
Journal | Int J Biochem Cell Biol |
Volume | 43 |
Issue | 10 |
Pagination | 1523-31 |
Date Published | 2011 Oct |
ISSN | 1878-5875 |
Palabras clave | Cell Adhesion Molecules, Cells, Cultured, Codon, Nonsense, Fibroblasts, Focal Dermal Hypoplasia, Helix-Loop-Helix Motifs, Humans, Protein Multimerization, Repressor Proteins, Skin Diseases, Transcriptional Activation, Twist Transcription Factor |
Abstract | Setleis Syndrome (OMIM ID: 227260) is a rare autosomal recessive disease characterized by abnormal facial development. Recently, we have reported that two nonsense mutations (c.486C>T [Q119X] and c.324C>T [Q65X]) of the basic helix-loop-helix (bHLH) transcription factor TWIST2 cause Setleis Syndrome. Here we show that periostin, a cell adhesion protein involved in connective tissue development and maintenance, is down-regulated in Setleis Syndrome patient fibroblast cells and that periostin positively responds to manipulations in TWIST2 levels, suggesting that TWIST2 is a transactivator of periostin. Functional analysis of the TWIST2 mutant form (Q119X) revealed that it maintains the ability to localize to the nucleus, forms homo and heterodimers with the ubiquitous bHLH protein E12, and binds to dsDNA. Reporter gene assays using deletion constructs of the human periostin promoter also reveal that TWIST2 can activate this gene more specifically than Twist1, while the Q119X mutant results in no significant transactivation. Chromatin immunoprecipitation assays show that both wild-type TWIST2 and the Q119X mutant bind the periostin promoter, however only wild-type TWIST2 is associated with higher levels of histone acetylation across the 5'-regulatory region of periostin. Taken together, these data suggest that the C-terminal domain of TWIST2, which is missing in the Q119X mutant form of TWIST2, is responsible for proper transactivation of the periostin gene. Improper regulation of periostin by the mutant form of TWIST2 could help explain some of the soft tissue abnormalities seen in these patients therefore providing a genotype-phenotype relationship for Setleis Syndrome. |
DOI | 10.1016/j.biocel.2011.07.003 |
Alternate Journal | Int. J. Biochem. Cell Biol. |
PubMed ID | 21801849 |
PubMed Central ID | PMC3163740 |
Grant List | 5P20RR011126 / RR / NCRR NIH HHS / United States DK073781 / DK / NIDDK NIH HHS / United States G12 RR003051 / RR / NCRR NIH HHS / United States G12 RR003051-20 / RR / NCRR NIH HHS / United States NCRR-G12RR03051 / / PHS HHS / United States P20 RR011126 / RR / NCRR NIH HHS / United States P20 RR011126-13 / RR / NCRR NIH HHS / United States P20 RR015555 / RR / NCRR NIH HHS / United States P20 RR015555-10 / RR / NCRR NIH HHS / United States P20 RR15555 / RR / NCRR NIH HHS / United States P20-RR016470 / RR / NCRR NIH HHS / United States R01 DK073871 / DK / NIDDK NIH HHS / United States R01 DK073871-05 / DK / NIDDK NIH HHS / United States R25 GM061838 / GM / NIGMS NIH HHS / United States R25 GM061838-09S1 / GM / NIGMS NIH HHS / United States R25 GM061838-10S1 / GM / NIGMS NIH HHS / United States R25 GM061838-12 / GM / NIGMS NIH HHS / United States R25GM061838 / GM / NIGMS NIH HHS / United States |