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

Abstract

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...

Congenital central hypoventilation syndrome and the PHOX2B gene: A model of respiratory and autonomic dysregulation

“…While these individuals are often diagnosed in infancy and childhood, they can remain undiagnosed even to adulthood. In these individuals, discovery of hypoventilation may, at times, require an environmental cofactor such as sedation, anesthesia, anticonvulsants, severe respiratory illness, treated obstructive sleep apnea (Antic et al, 2006; Weese-Mayer et al, 2005) or the homozygous condition (Trochet et al, 2008) to elicit overt clinical events like hypoventilation and/or respiratory arrest. Thus far, fewer than 50 LO-CCHS cases have been reported, but considering the subtlety of the clinical profile in those cases, the prevalence in the general population is likely to be significantly higher than suggested by these few cases.…”

PHOX2B mutations in patients with Ondine–Hirschsprung disease and a review of the literature

“…However, array-CGH analysis revealed an interstitial microduplication of Xq28 encompassing the MECP2 gene, and further workup such as a search for Xq28 duplications is recommended for CCHS patients without PHOX2B or RET mutations [4]. The +4 alanine repeat mutation was previously identified in only two reports [15,16]. One described a CCHS patient harboring a homozygous mutation that was below the phenotypic threshold for dominant CCHS and that behaved as a recessive allele, while both heterozygous carrier parents were asymptomatic.…”

“…Contractions of the alanine tract by −3, −4, −5, −7, and −13 are rare variations in normal individuals but do not appear to cause CCHS [1,12,14]. The smallest polyalanine expansions were +4, and 20/25, 20/26, and 20/27 are the most common genotypes in CCHS patients [16,21].…”

Association analysis of the PHOX2B gene with Hirschsprung disease in the Han Chinese population of Southeastern China

“…The same 15-nucleotide deletion in the PHOX2B gene was discovered in normal Japanese individuals and also in patients with schizophrenia and exotropia [21]. In that study, it was concluded that the 15-nucleotide deletion was not associated with the development of exotropia in schizophrenic patients [21,22]. The 15-nucleotide deletion in PHOX2B results in the loss of 5 alanine residues in the alanine repeat of the protein, and the protein function remains at 60% of normal levels.…”