Compound effect of <i>PHOX2B</i> and <i>RET</i> gene variants in congenital central hypoventilation syndrome combined with Hirschsprung disease

Fitze, Guido; König, Inke R.; Paditz, Ekkehart; Serra, Alexandre; Schläfke, Marianne E.; Roesner, D.; Ziegler, Andreas; Schackert, Hans K.

doi:10.1002/ajmg.a.32300

Cited by 27 publications

(17 citation statements)

References 22 publications

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“…21 In this study, all of the PHOX2b mutations were found in NB patients with concomitant CCHS, and possibly should be associated with the latter and not the former. Such incidence of PHOX2b variants in patients with both NB and CCHS is similar to that found in patients with CCHS and HSCR, 22,23 suggesting that in NB another yet unknown gene might interact with PHOX2b producing the tumor phenotype. Clearly, the genetic background of hereditary and sporadic NB is rather complex and does not seem dependent on single-gene mutations, rather suggesting an oligogenic model of disease transmission, which involves more loci in the genetic determination of the disease and is similar to that found in HSCR patients.…”

Section: Discussionmentioning

confidence: 50%

Rare Occurrence of PHOX2b Mutations in Sporadic Neuroblastomas

Serra

Häberle²,

König³

et al. 2008

Journal of Pediatric Hematology/Oncology

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Neuroblastomas (NBs) are frequent solid tumors in childhood for which no specific genetic marker linked to their development has been identified to date. PHOX2b, which regulates the autonomic neuron development, has been associated with the development of autonomic diseases, and has been considered a potential candidate gene for neural crest-derived tumors such as NB. To ascertain the role of the PHOX2b gene in NB development, we have sequenced the complete PHOX2b coding region in tumors from 69 patients with sporadic NB, while 130 blood donors served as negative controls and 9 NB cell lines as positive controls. We found a missense deletion in exon 3 in a cell line. A further silent mutation in exon 3 (c.870C>A) was observed in 3 tumors but in none of the controls. A new polymorphism in intron 1 (IVS1-114 G>A) was observed in 31 tumor samples (44.9%) and in 68 controls (52.3%). We did not find any conclusive association of the polymorphisms or mutations in PHOX2b with the development of NB, although the large confidence intervals neither substantiate nor exclude a role for this gene in the tumor etiology.

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Section: Discussionmentioning

confidence: 50%

Rare Occurrence of PHOX2b Mutations in Sporadic Neuroblastomas

Serra

Häberle²,

König³

et al. 2008

Journal of Pediatric Hematology/Oncology

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“…Syndromic cases of HD were excluded. None of the HD patients harbored a paired-like homeobox 2b (PHOX2B) mutation [17]. The diagnosis of HAEC was made if the child had abdominal distension, explosive stools, diarrhea, radiological evidence of bowel obstruction, and no other definable cause.…”

Section: Subjectsmentioning

confidence: 99%

Hirschsprung-associated enterocolitis develops independently of NOD2 variants

Lacher

Fitze

Helmbrecht

et al. 2010

Journal of Pediatric Surgery

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“…Neither the frameshift mutations nor the alanine expansions were detected in 130 normal controls. The full characterisation of the PHOX2b variants in our cohort of CCHS/HSCR patients has been published (Fitze et al, 2008). The summary of the data is presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, RET has been considered a modifier factor for PHOX2b mutations in the HSCR phenotype in patients with CCHS/HSCR (De Pontual et al, 2006), and a compound effect of PHOX2b and RET seems to contribute to the combined CCHS/HSCR phenotype (Fitze et al, 2008). A significant over-representation of the RET c.135A variant has also been shown in a series of 33 CCHS patients (Fitze et al, 2003b), and even animal models attempting to recreate the CCHS phenotype have demonstrated that an association of genes involved in neural crest development may be associated in disturbances of the respiratory control system, since RET, GDNF, EDN-1, BDNF and EDN-ra heterozygous knock-out mice showed abnormalities in the hypoxic and hypercapnic ventilatory responses .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, other variants in genes from the Endothelin-and RET-pathways have also been found in CCHS, which is particularly important since CCHS is often associated with autonomic diseases such as HSCR (Gaultier et al, 2004). Our group has recently published a study on the compound effects of PHOX2b and RET variants in CCHS and CCHS/HSCR patients, showing that PHOX2b is the main gene responsible for CCHS, yet PHOX2b and RET contribute to the combined CCHS/HSCR phenotype (Fitze et al, 2008). Accordingly, a study by Sasaki et al looking and associated genes (GDNF,GFRA1,PHOX2a,PHOX2b,EDN1,EDN3,EDNRB,and BDNF) in seven patients with isolated CCHS and three patients with HSCR showed several mutations of RET, GFRA1, PHOX2a, and HASH-1 genes in patients with or without mutations of the PHOX2b gene (Sasaki et al, 2003), while RET has also been associated with the CCHS phenotype (independently from PHOX2b) in two further studies (Sakai et al, 2001;Kanai et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of RET, ZEB2, EDN3 and GDNF Genomic Rearrangements in Central Congenital Hyperventilation Syndrome Patients by Multiplex Ligation‐dependent Probe Amplification

Serra

Görgens

Alhadad

et al. 2010

Annals of Human Genetics

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SummaryCentral congenital hypoventilation syndrome (CCHS) is an autonomous control disease producing hypoventilation, high PaCO 2 , and low PaO 2 during quiet sleep. The main gene variants detected in CCHS are mutations in the PHOX2b gene in up to 97% of isolated cases. However, CCHS is sometimes associated with autonomic diseases such as Hirschsprung disease (HSCR). Since genomic rearrangements in particularly sensitive areas of the RET protooncogene and/or associated genes may account for the CCHS/HSCR phenotype in patients without other detectable RET variants, the aim of the present study was to identify rearrangements in the coding sequence of RET as well as in three HSCR-associated genes (ZEB2, EDN3 and GDNF) in CCHS/HSCR patients by using Multiplex Ligation-dependent Probe Amplification (MLPA). We have screened 27 CCHS and 11 CCHS/HSCR patients for genomic rearrangements in RET, ZEB2, EDN3 and GDNF and did not identify any deletion or amplification in these four genes in all patients. We conclude that genomic rearrangements in RET are rare and were not responsible for the CCHS/HSCR phenotype in individuals without identifiable germline RET variants in our group of patients, yet this possibility cannot be excluded altogether given the size of the cohort.

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Compound effect of PHOX2B and RET gene variants in congenital central hypoventilation syndrome combined with Hirschsprung disease

Cited by 27 publications

References 22 publications

Rare Occurrence of PHOX2b Mutations in Sporadic Neuroblastomas

Rare Occurrence of PHOX2b Mutations in Sporadic Neuroblastomas

Hirschsprung-associated enterocolitis develops independently of NOD2 variants

Analysis of RET, ZEB2, EDN3 and GDNF Genomic Rearrangements in Central Congenital Hyperventilation Syndrome Patients by Multiplex Ligation‐dependent Probe Amplification

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