Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome

Bachetti, Tiziana; Matera, Ivana; Borghini, Silvia; Duca, Marco Di; Ravazzolo, Roberto; Ceccherini, Isabella

doi:10.1093/hmg/ddi188

Cited by 109 publications

(123 citation statements)

References 33 publications

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“…These observations are consistent with the results obtained with FOXL2 and point to a common pathogenic mechanism. A similar behavior has been observed for PHOX2B in cellular models (Bachetti et al, 2005;Trochet et al, 2005 A c c e p t e d M a n u s c r i p t 8 expansion in Arx transcription factor forms intranuclear inclusions and results in increased cell death suggesting a toxic effect (Nasrallah et al, 2004). Thus, it appears that this expansion lead to cellular toxicity as it was suggested for PABPN1.…”

Section: Mutations Affecting the Foxl2 Locussupporting

confidence: 73%

The mutations and potential targets of the forkhead transcription factor FOXL2

Moumné

Batista

Benayoun

et al. 2008

Molecular and Cellular Endocrinology

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Abstract.Mutations of FOXL2, a gene encoding a forkhead transcription factor, have been shown to cause the blepharophimosis-ptosis-epicanthus inversus (BPES) syndrome. This genetic disorder is characterized by eyelid and mild craniofacial abnormalities that can appear associated with premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. In this review we summarize recent data concerning FOXL2, its mutations and its potential targets. Indeed, many mutations have been described in the coding sequence of FOXL2. Among them, polyAlanine expansions and premature nonsense mutations have been shown to induce protein aggregation. In the context of the ovary, FOXL2 has been suggested to be involved in the regulation of cholesterol and steroid metabolism, apoptosis, reactive oxygen species detoxification and inflammation processes. The elucidation of the impact of FOXL2 mutations on its function will allow a better understanding of the pathogenic mechanisms underlying the BPES phenotype.

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Section: Mutations Affecting the Foxl2 Locussupporting

confidence: 73%

The mutations and potential targets of the forkhead transcription factor FOXL2

Moumné

Batista

Benayoun

et al. 2008

Molecular and Cellular Endocrinology

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“…Alanine expansions may result in a protein that can bind to the correct targets in the genome but is unable to carry out its normal regulatory function and, therefore, competes with the product of the wild-type allele (4). In contrast, a single functional Phox2b allele may ensure correct protein function, leading to a less severe phenotype (8).…”

Section: Discussionmentioning

confidence: 99%

Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factorPhox2b

Ramanantsoa¹,

Vaubourg²,

Dauger³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Heterozygous mutations of the transcription factor PHOX2B have been found in most patients with central congenital hypoventilation syndrome, a rare disease characterized by sleep-related hypoventilation and impaired chemosensitivity to sustained hypercapnia and sustained hypoxia. PHOX2B is a master regulator of autonomic reflex pathways, including peripheral chemosensitive pathways. In the present study, we used hyperoxic tests to assess the strength of the peripheral chemoreceptor tonic drive in Phox2bϩ/Ϫ newborn mice. We exposed 69 wild-type and 67 mutant mice to two hyperoxic tests (12-min air followed by 3-min 100% O2) 2 days after birth. Breathing variables were measured noninvasively using whole body flow plethysmography. The initial minute ventilation decrease was larger in mutant pups than in wild-type pups: Ϫ37% (SD 13) and Ϫ25% (SD 18), respectively, P Ͻ 0.0001. Furthermore, minute ventilation remained depressed throughout O2 exposure in mutants, possibly because of their previously reported impaired CO2 chemosensitivity, whereas it returned rapidly to the normoxic level in wild-type pups. Hyperoxia considerably increased total apnea duration in mutant compared with wild-type pups (P ϭ 0.0001). A complementary experiment established that body temperature was not influenced by hyperoxia in either genotype group and, therefore, did not account for genotype-related differences in the hyperoxic ventilatory response. Thus partial loss of Phox2b function by heterozygosity did not diminish the tonic drive from peripheral chemoreceptors.control of breathing; chemosensitivity; apnea CENTRAL CONGENITAL HYPOVENTILATION syndrome (CCHS or Ondine's curse) is a rare disease, generally present from birth and characterized by hypoventilation during sleep in the absence of primary neuromuscular or lung disease or of brain stem lesions (3). Throughout life, patients with CCHS have absent or markedly reduced ventilatory responses to sustained hypercapnia (29) and, to a lesser extent, to sustained hypoxia (29). These respiratory impairments are generally ascribed to impaired central integration of chemosensory inputs at the brain stem level, rather than to failure of chemoreceptor activity, which is at least partially present (15,22,37). The genetic basis for CCHS was discovered recently: most patients with CCHS have a heterozygous mutation of the PHOX2B gene (2,23,41,43). PHOX2B is a master regulator of the noradrenergic phenotype and of all neuronal relays of autonomic medullary reflex pathways (30), including peripheral chemosensitive pathways (9).Mice with a single functional Phox2b allele (i.e., Phox2bϩ/Ϫ mice) provide a unique opportunity to investigate the genotype-phenotype relationship in CCHS. Our laboratory's previous studies showed that Phox2bϩ/Ϫ mice had longer sleep apnea times than their wild-type littermates on postnatal day (P) 5 (P5) (11) and a weaker response to CO 2 on P2, followed by normalization before P10 (9). These ventilatory impairments were reminiscent of CCHS. However, the hyperpneic response t...

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“…Previous studies have shown that all alanine expansions tested lead to protein misfolding in vitro, resulting in cytoplasmic aggregation visible in HeLa cells only for proteins with more than a + 9 alanine expansion in our experiments (Bachetti et al, 2005;Trochet et al, 2005a). However, a gel filtration experiment indicated that PHOX2B expanded by only 5 alanines had a strong tendency to multimerize in vitro (Figure 2; Trochet et al, 2005a).…”

Section: Phox2b Expanded By 4 Alanines Does Not Multimerize In Vitromentioning

confidence: 45%

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

Trochet

Pontual

Estêvão³

et al. 2008

Hum. Mutat.

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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...

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Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome

Cited by 109 publications

References 33 publications

The mutations and potential targets of the forkhead transcription factor FOXL2

The mutations and potential targets of the forkhead transcription factor FOXL2

Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factorPhox2b

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

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