<i>PMX2B</i>, a new candidate gene for Hirschsprung's disease

Benailly, Houda Karmous; Lapierre, Jean-Michel; Laudier, Béatrice; Amiel, Jeanne; Attié, T; Blois, Marie Christine De; Vekemans, Michel; Romana, Serge

doi:10.1034/j.1399-0004.2003.00105.x

Cited by 52 publications

(30 citation statements)

References 22 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, tumors in familial cases of neuroblastoma showed neither mutations of the second allele nor loss of heterozygosity, suggesting that gain-of-function or dominant-negative effects may account for the oncogenic effects (Bourdeaut et al, 2005). The absence of tumors in response to a heterozygous deletion of the PHOX2B locus (Benailly et al, 2003), also argues against a loss-of-function effect in neuroblastoma predisposition.…”

Section: Introductionmentioning

confidence: 94%

Neuroblastoma Phox2b Variants Stimulate Proliferation and Dedifferentiation of Immature Sympathetic Neurons

Reiff¹,

Tsarovina²,

Majdazari³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. A Phox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage.

show abstract

Section: Introductionmentioning

confidence: 94%

Neuroblastoma Phox2b Variants Stimulate Proliferation and Dedifferentiation of Immature Sympathetic Neurons

Reiff¹,

Tsarovina²,

Majdazari³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The phox2b gene has three exons spanning 3.1 kb; it encodes a paired homeobox transcription factor whose expression is both critical for autonomic neuron specification and tightly controlled (Pattyn et al 1997(Pattyn et al , 1999Amiel et al 2003;Benailly et al 2003;Trochet et al 2005).…”

mentioning

confidence: 99%

Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b

et al. 2007

View full text Add to dashboard Cite

Despite its recognized utility, the extent to which evolutionary sequence conservation-based approaches may systematically overlook functional noncoding sequences remains unclear. We have tiled across sequence encompassing the zebrafish phox2b gene, ultimately evaluating 48 amplicons corresponding to all noncoding sequences therein for enhancer activity in zebrafish. Post hoc analyses of this interval utilizing five commonly used measures of evolutionary constraint (AVID, MLAGAN, SLAGAN, phastCons, WebMCS) demonstrate that each systematically overlooks regulatory sequences. These established algorithms detected only 29%-61% of our identified regulatory elements, consistent with the suggestion that many regulatory sequences may not be readily detected by metrics of sequence constraint. However, we were able to discriminate functional from nonfunctional sequences based upon GC composition and identified position weight matrices (PWM), demonstrating that, in at least one case, deleting sequences containing a subset of these PWMs from one identified regulatory element abrogated its regulatory function. Collectively, these data demonstrate that the noncoding functional component of vertebrate genomes may far exceed estimates predicated on evolutionary constraint.

show abstract

“…In some cases, haploinsufficiency is the most likely mechanism (HOXA13, Innis et al, 2004). A dominant negative effect is unlikely in X-linked conditions (XLAG and XLMR-GH) as opposed to synpolydactyly (SPD) and CCHS, where a deletion encompassing the gene leads to a phenotype distinct to the one observed with alanine expansions (Benailly et al, 2003;Goodman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Homozygous mutation of the PHOX2B gene in congenital central hypoventilation syndrome (Ondine's Curse)

Trochet

Pontual

Estêvão³

et al. 2008

Hum. Mutat.

View full text Add to dashboard Cite

Homozygosity for a dominant allele is relatively rare and preferentially observed in communities with high inbreeding. According to the definition of true dominance, similar phenotypes should be observed in patients heterozygous and homozygous for a dominant mutation. However, the homozygous phenotype usually tends to be more severe than the heterozygous one. In these cases, the wild-type and mutant alleles are semi-dominant. Here we report a patient with a Congenital Central Hypoventilation Syndrome (CCHS) phenotype and homozygosity for a PHOX2B gene mutation leading to an alanine expansion shorter than the threshold hitherto observed in CCHS patients with a heterozygous mutation. This observation adds the concept of mutational threshold per se to the discussion about dominant and recessive alleles. © 2008 Wiley-Liss, Inc.KEY WORDS: PHOX2B, CCHS, homozygous alanine expansion INTRODUCTIONHomopolymeric tracts of amino acids are extremely abundant in eukaryotic proteins (Green and Wang, 1994). In humans, 20% of proteins contain at least one such tract (Karlin et al., 2002). They have recently been proposed to be a major source of phenotypic variation in evolution (Fondon and Garner, 2004). Polyalanine tracts varying in length from 5 to 20 repeats have been predicted in roughly 500 human proteins, with over-representation among transcription factors (Lavoie et al., 2003). Alanine tracts are encoded by imperfect tri-nucleotide repeats (GCN) and length polymorphisms can be observed in controls (Lavoie et al., 2003). Unequal allelic homologous recombination and/or DNA loop formation during meiosis and mitosis may cause alanine expansions and contractions (Trochet et al., 2007;Warren, 1997). The function of polyalanine stretches is still unknown. In all cases but one (PABPN1), polyalanine expansion mutations in human diseases have involved transcription factors Trochet et al. PHOX2B, HOXA13, HOXD13, RUNX2, ZIC2, FOXL2, ARX, and SOX3) (Table1). The mechanisms by which alanine expansion lead to disease may include loss-of-function, a dominant negative effect, or a gain of toxic function (Albrecht and Mundlos, 2005). (Congenital Central Hypoventilation Syndrome (CCHS) is a life-threatening condition that results from abnormal autonomic control of breathing and is ascribed to heterozygous PHOX2B (MIM# 603851) gene mutations. Various mutations have been described, i.e. polyalanine expansions, missense and frameshift mutations Weese-Mayer et al., 2003;Matera et al., 2004). Polyalanine expansions are by far the most frequent mutations with an expansion ranging from +5 to +13 alanines. Genotype/phenotype correlations on large series showed that i) patients with a +5 alanine expansion do not present Hirschsprung disease as an associated feature (Trochet et al., 2005b), ii) the longer the expansion, the more severe the ventilatory phenotype (Matera et al., 2004) and, iii) tumours of the sympathetic nervous system are rarely found with alanine expansions (Trochet et al., 2005b). Polyalanine contractions of -5, -7 and -13 alanines...

show abstract

PMX2B, a new candidate gene for Hirschsprung's disease

Cited by 52 publications

References 22 publications

Neuroblastoma Phox2b Variants Stimulate Proliferation and Dedifferentiation of Immature Sympathetic Neurons

Neuroblastoma Phox2b Variants Stimulate Proliferation and Dedifferentiation of Immature Sympathetic Neurons

Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b

Homozygous mutation of the PHOX2B gene in congenital central hypoventilation syndrome (Ondine's Curse)

Contact Info

Product

Resources

About