Abstract
HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger.
| Original language | English |
|---|---|
| Pages (from-to) | 1770-1777 |
| Number of pages | 8 |
| Journal | Biochimica et Biophysica Acta - General Subjects |
| Volume | 1863 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2017 |
Fingerprint
Keywords
- Journal Article
Cite this
Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease. / Di Zanni, Eleonora; Adamo, Annalisa; Belligni, Elga; Lerone, Margherita; Martucciello, Giuseppe; Mattioli, Girolamo; Pini Prato, Alessio; Ravazzolo, Roberto; Silengo, Margherita; Bachetti, Tiziana; Ceccherini, Isabella.
In: Biochimica et Biophysica Acta - General Subjects, Vol. 1863, No. 7, 07.2017, p. 1770-1777.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease
AU - Di Zanni, Eleonora
AU - Adamo, Annalisa
AU - Belligni, Elga
AU - Lerone, Margherita
AU - Martucciello, Giuseppe
AU - Mattioli, Girolamo
AU - Pini Prato, Alessio
AU - Ravazzolo, Roberto
AU - Silengo, Margherita
AU - Bachetti, Tiziana
AU - Ceccherini, Isabella
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2017/7
Y1 - 2017/7
N2 - HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger.
AB - HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger.
KW - Journal Article
U2 - 10.1016/j.bbadis.2017.04.017
DO - 10.1016/j.bbadis.2017.04.017
M3 - Article
C2 - 28433712
VL - 1863
SP - 1770
EP - 1777
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
SN - 0304-4165
IS - 7
ER -