A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction

Jeyabalan, Nallathambi; Moumné, Lara; Baere, Elfride De; Beysen, Diane; Kim, Usha; Sundaresan, Periasamy; Veitia, Reiner A.

doi:10.1007/s00439-006-0276-0

Cited by 60 publications

(39 citation statements)

References 16 publications

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“…In fact, with respect to PHOX2B alanine expansion mutations, we observe a continuum from a recessive allele (+4 alanines) to a dominant allele with incomplete penetrance and variable expression (+5 alanines) and to fully penetrant dominant alleles (+6 alanines and above). Expression of the mutant FOXL2 allele in Cos-7 cells showed a higher cytoplasmic retention than the wild-type protein but no aggregation (Nallathambi et al, 2007). Here, no obvious tendency to oligomerization in vitro could be observed for the +4 alanine expansion, as opposed to other expansions (Trochet et al, 2005a).…”

Section: Discussionmentioning

confidence: 64%

“…Adding to the concept of continuous dysfunction according to the length of the alanine tract, are the phenotypes reported in patients with heterozygous contractions of HOXD13 and FOXL2 (Table 1, Zhao et al, 2007;Moumne et al, 2005). Recently, a homozygous alanine expansion has been reported in a patient with blepharophimosis-ptosisepicanthus inversus syndrome (BPES), ascribed to the FOXL2 gene (Table 1, Nallathambi et al, 2007). As in the case we report, the threshold of expansion was lower than the one leading to the phenotype in heterozygotes (+5 alanines versus +10 alanines in a row of 14 alanines) and heterozygous carriers were asymptomatic.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 64%

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.

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“…Recently, it was proposed that the pathogenic mechanism of this polyalanine expansion may be its mislocalisation (due to cytoplasmic aggregation) together with its inclusion into nuclear aggregates (Caburet et al 2004). We have recently identified a short homozygous polyalaline expansion (of 19 alalines instead of 14) in a consanguineous Indian pedigree, resulting in a recessive form of BPES and ovarian dysfunction (Nallathambi et al 2007). The findings in our family lend further support to the genotype-phenotype correlation for this type of mutation (polyalanine expansion).…”

Section: Resultsmentioning

confidence: 99%

FOXL2 mutations in Indian families with blepharophimosis-ptosis-epicanthus inversus syndrome

Jeyabalan

Neethirajan

Kim

et al. 2007

J Genet

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“…An Ala26 protein has been described in a BPES patient with an important ovarian cyst [20]. We have recently described a homozygous mutation leading to Ala19 in a consanguineous BPES family [21].…”

Section: Foxl2 Mutations In Bpesmentioning

confidence: 96%

The transcription factor FOXL2 in ovarian function and dysfunction.

Baere

Fellous²,

Veitia³

2010

Folia Histochem Cytobiol.

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Abstract:The Blepharophimosis Ptosis Epicanthus-inversus Syndrome is a genetic disease characterized by complex eyelid malformations often associated with premature ovarian failure (POF). BPES is basically an autosomal dominant disease, due to mutations in the FOXL2 gene, which encodes a forkhead transcription factor. More than one hundred mutations of FOXL2 have been described to date. In agreement with the BPES phenotype, FOXL2 is expressed (though not exclusively) in the developing eyelids and in fetal and adult ovaries. Two mouse knock-out models have been produced. They recapitulate the BPES phenotype and have provided insights into the pathology. Loss-of-function mutations in FOXL2 are predicted to lead to BPES and POF, while hypomorphic mutations might lead to BPES without ovarian dysfunction. However, exceptions to the genotype-phenotype correlation have been described. To better understand the pathogenic effect of these mutations it is crucial to study the normal regulation of FOXL2 and its targets. We briefly address these aspects in this review and hope that basic research around FOXL2 will eventually lead to uncover new therapeutic avenues.

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A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction

Cited by 60 publications

References 16 publications

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

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

FOXL2 mutations in Indian families with blepharophimosis-ptosis-epicanthus inversus syndrome

The transcription factor FOXL2 in ovarian function and dysfunction.

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