Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome

Yamada, Tetsuya; Hayasaka, Seiji; Matsumoto, Masayuki; Budu,; Esa, Tenri; Hayasaka, Yoriko; Endo, Machi

doi:10.1007/s100380170009

Cited by 13 publications

(9 citation statements)

References 8 publications

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“…There is a proline tract at this position and the mutation results in a H291fsX361 frameshift truncating the predicted protein. A deletion mutation involving the same bases has been reported in a Japanese BPES patient [Yamada et al, 2001]. Two additional changes were also observed in this individual.…”

Section: P Y a S C Q M A A A A A A A A A A A A A A G P G S P G A A A supporting

confidence: 68%

Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients

et al. 2003

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Bleparophimosis ptosis epicanthus inversus syndrome (BPES) is a rare disorder characterized by eyelid malformation and in some cases associated with premature ovarian failure. Although the familial form is autosomal dominant, many cases are also sporadic. The mutations causing this disorder were found in a winged/forkhead transcription factor gene named FOXL2. We have sequenced the mouse homolog for the FOXL2 gene and identified the Fugu rubripes (pufferfish) ortholog from the database. By alignment of the three sequences, we found an almost complete conservation of the forkhead domain in the three species. There is 95% and 61% conservation at the protein level between human-mouse and human-pufferfish, respectively. The polyalanine and polyproline tracts within the gene are absent in Fugu rubripes. An overview identifies four breaks in the conservation of the gene within these species. Using a direct sequencing approach, we performed mutation analysis from DNA of nine affected individuals from familial and sporadic cases. The mutations are distributed throughout the coding region of the FOXL2 gene. We identified five novel mutations: g.292delG (E19fsX149); g.530G>A (W98X); g.548A>G (H104R); g.652G>T (E139X); and g.1178_1185del8 (A314fsX530). In addition we also identified two known mutations g.823C>T (Q196X) and g.1092_1108dup17, the latter in individuals from three unrelated pedigrees.

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Section: P Y a S C Q M A A A A A A A A A A A A A A G P G S P G A A A supporting

confidence: 68%

Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients

et al. 2003

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“…To date, a total of 106 unique intragenic FOXL2 mutations (i.e. different mutations that are unique to the world-wide collection of gene variants) have been identified in 206 unrelated BPES families from different ethnic origin [Bell et al, 2001;Cha et al, 2003;Crisponi et al, 2001Crisponi et al, , 2002De Baere et al, 2001Dollfus et al, 2003;Fokstuen et al, 2003;Kosaki et al, 2002;Kumar et al, 2004;Li et al, 2005;Nallathambi et al, 2007Nallathambi et al, , 2008Or et al, 2006;Raile et al, 2005;Ramírez-Castro et al, 2002;Tang et al, 2006;Udar et al, 2003;Vincent et al, 2005;Yamada et al, 2001] (this study). An overview of these mutations is presented in Supplementary Table S1 (available online at http://www.…”

Section: Mutation Spectrum Intragenic Foxl2 Mutations In Bpesmentioning

confidence: 89%

FOXL2mutations and genomic rearrangements in BPES

2009

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The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF.

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“…3(b)]. A previously reported in-frame 30 bp duplication (909-938dup30) was found in Patients 3,4,11,12,13,14,15, and 24 in four families and one sporadic case [ Fig. 3(c)].…”

Section: Resultsmentioning

confidence: 73%

“…Furthermore, a classification of FOXL2 mutations, according to their effects on the putative proteins, has been proposed and two mutational hotspots (909-938dup30 and 1080-1096dup17) were identified (13). Recently, several FOXL2 mutations were reported in BPES patients (14)(15)(16)(17)(18)(19).…”

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confidence: 99%

Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis–ptosis–epicanthus inversus syndrome

C.¹,

Jang

Lee

et al. 2003

Clinical Genetics

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We screened for mutations in the forkhead transcription factor gene, FOXL2, in Korean patients with sporadic or familial blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) and direct sequencing. Five of nine BPES families and three of seven sporadic cases were detected to have FOXL2 mutations. We identified four types of FOXL2 mutations, two of which are novel. A new 14 bp deletion (939-952del14) causing a frameshift from G235W and the extension of the predicted protein to 527 amino acids was detected in a BPES family patient. In addition, a novel 845C > A transversion, resulting in a nonsense mutation (S203X), was found in a sporadic case of BPES. The previously reported in-frame 30 bp duplication (909-938dup30) was the most common mutation and was found in eight patients of four BPES families and one sporadic case. A known 17 bp duplication (1080-1096dup17) was observed in a sporadic BPES case. We were unable to find a causal mutation in four BPES families and four sporadic cases. These results suggest that in a fraction of BPES patients, the genetic defect might be associated with a mutation in the non-coding region of the FOXL2 gene or in other genes.

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Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome

Cited by 13 publications

References 8 publications

Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients

Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients

FOXL2mutations and genomic rearrangements in BPES

Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis–ptosis–epicanthus inversus syndrome

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