PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Department of Pediatrics and Children's Research Institute, Milwaukee, WI, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 05/2012; 20(12). DOI: 10.1038/ejhg.2012.80
Source: PubMed


Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.European Journal of Human Genetics advance online publication, 9 May 2012; doi:10.1038/ejhg.2012.80.

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Available from: Kala F Schilter, Apr 11, 2014
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    • ") c.289_290del p.R97Gfs*101 6 HD (D'haene, et al., 2011) c.301C>T p.Q101* 6 (D'haene, et al., 2011) c.304C>T p.Q102* 6 (D'haene, et al., 2011) c.313C>G p.L105V 6 (Phillips, 2002) c.323A>C p.N108T 6 (Phillips, 2002) c.356del p.Q119Rfs*36 6 (Perveen, et al., 2000) c.363C>A p.Y121* 6 (Vieira, et al., 2006) c.366del p.D122Efs*33 6 (Saadi et al., 2001) c.398G>A p.W133* 6 (Semina, et al., 1996) c.410G>T p.G137V 6 (Kniestedt et al., 2006) c.416del p.T139Nfs*16 6 (Strungaru, et al., 2007) c.500dup p.P168Tfs*31 6 (Perveen, et al., 2000) c.652_653delinsAAG p.Y218Qfs*11 6 (Perveen, et al., 2000) c.662_669dup p.P224Rfs*18 6 (Vieira, et al., 2006) c.679del p.Y227Mfs*12 6 (Brooks et al., 2004) c.690del p.C231Vfs*8 6 (Borges et al., 2002) c.698C >T p.S233L 6 OAR (Kelberman et al., 2011) c.708_730del p.S237Afs *48 6 OAR (Reis, et al., 2012 "
    Dataset: ESM
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    • "PITX2 and LMX1B cause syndromic forms of developmental glaucoma (Rieger syndrome and Nail-Patella syndrome, respectively). Approximately 50% of patients with PITX2 mutations develop glaucoma (Reis et al. 2012). Recently , mutations involving a genomic region distal to PITX2 have been identified as disease causing (Volkmann et al. 2011). "
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    ABSTRACT: The characterization of genes responsible for glaucoma is the critical first step toward the development of gene-based diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. Early-onset forms of glaucoma affecting children and young adults are typically inherited as Mendelian autosomal dominant or recessive traits whereas glaucoma affecting older adults has complex inheritance. In this report, we present a comprehensive overview of the genes and genomic regions contributing to inherited glaucoma.
    Cold Spring Harbor Perspectives in Medicine 09/2014; 4(12). DOI:10.1101/cshperspect.a017244 · 9.47 Impact Factor
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    • "Previous genetic screens in the ocular disease cohort included FOXE3 (forkhead box E3), CYP1B1 (cytochrome P4501B1), B3GALTL (beta-1,3-galactosyltransferase-like), PITX2 (pituitary paired-like homeodomain transcription factor 2), FOXC1 (forkhead box C1), and PITX3 (paired-like homeodomain 3) [33-37]. "
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    ABSTRACT: The migratory neural crest cell population makes a significant contribution to the anterior segment structures of the eye. Consequently, several anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. The forkhead box D3 (FOXD3) gene encodes a forkhead transcription factor that plays an important role in neural crest specification in vertebrates and therefore may be involved in human eye disease. We screened 310 probands with developmental ocular conditions for variations in FOXD3. Six nonsynonymous FOXD3 variants were identified. Four of these changes, c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), and c.818_829dup (p.Arg273_Gly276dup), affected conserved regions and were observed primarily in probands with aniridia or Peters anomaly; out of these four variants, one, p.Arg273_Gly276dup, was not detected in control populations and two, p.Pro120Leu and p.Asn173His, were statistically enriched in cases with aniridia or Peters anomaly. The p.Arg273_Gly276dup variant was seen in a proband with aniridia as well as two additional unrelated probands affected with anophthalmia or congenital cataracts. The p.Asn173His variant affects Helix 2 of the DNA-binding domain and was observed in two unrelated patients with Peters anomaly or aniridia; in both cases, one parent carried the same allele. FOXD3 variants increase the risk of anterior segment dysgenesis phenotypes in humans. The p.Asn173His mutation affects a residue in the forkhead domain that is 100% conserved among vertebrate orthologs and is predicted to participate in protein-protein interactions. Its phenotypic effects may be modulated by transcriptional cofactors which have yet to be identified.
    Molecular vision 06/2012; 18:1740-9. · 1.99 Impact Factor
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