Genetic Analysis of PITX2 and FOXC1 in Rieger Syndrome Patients From Brazil

Borges, Adriana Silva; Susanna, Remo; Carani, José Carlos Eudes; Betinjane, Alberto Jorge; Alward, Wallace L.M.; Stone, Edwin M.; Sheffield, Val C.; Nishimura, Darryl

doi:10.1097/00061198-200202000-00010

Cited by 41 publications

(19 citation statements)

References 4 publications

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“…This mutation occurs in the middle of a 14-amino-acid-conserved domain of yet unknown function 6 providing further support for the functional significance of this motif. Finally, the c.253-11 A4G mutation in PITX2 in three of our cases appears to represent a 'hot spot' as it has now been reported in six independent families (cases 7-9, our study; 6,10,31 ). Two of our three probands carrying this mutation have atypical ocular phenotypes.…”

Section: Foxc1 Mutations: Phenotypes and Genotypessupporting

confidence: 76%

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Reis¹,

Tyler²,

et al. 2012

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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.

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Section: Foxc1 Mutations: Phenotypes and Genotypessupporting

confidence: 76%

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Reis¹,

Tyler²,

et al. 2012

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“…Identified by Semina et al ,27 PITX2 , at 4q25, was the first locus associated with ARS and mutations can be identified in 10–60% of probands affected with ARS 28 29. Mutations in FOXC1 at 6p25 associated with ARS were identified in about half affected probands in a single series 30.…”

Section: Molecular Geneticsmentioning

confidence: 98%

Axenfeld-Rieger syndrome: new perspectives: Figure 1

et al. 2011

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Axenfeld-Rieger syndrome is a genetic disease affecting multiple organ systems. In the eye, this condition manifests with varying degrees of anterior segment dysgenesis and carries a high risk of glaucoma. Other associated systemic issues include cardiovascular outflow tract malformations, craniofacial abnormalities and pituitary abnormalities, which can result in severe endocrinological sequelae. Recent advances in molecular genetics have identified two major genes, PITX2 and FOXC1, demonstrating a wide spectrum of mutations, which aids in the molecular diagnosis of the disease, although evidence exists to implicate other loci in this condition. The management of individuals affected by Axenfeld-Rieger syndrome requires a multidisciplinary approach and would include dedicated surveillance and management of glaucoma, sensorineural hearing loss, and cardiac, endocrinological, craniofacial and orthopaedic abnormalities.

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“…Furthermore, systematic analysis of dental anomalies in patients with PITX2 mutation has not been carried out. Reports of PITX2 mutations provide very limited information on the dental phenotype [Semina et al, 1996;Alward et al, 1998;Kulak et al, 1998;Perveen et al, 2000;Saadi et al, 2001;Borges et al, 2002;Phillips, 2002;Wang et al, 2003]. Better classification of the dental phenotypes associated with PITX2 mutations may lead to more definitive diagnosis of patients likely to carry PITX2 mutations.…”

Section: Introductionmentioning

confidence: 99%

A novel homeobox mutation in thePITX2gene in a family with Axenfeld‐Rieger syndrome associated with brain, ocular, and dental phenotypes

Idrees

Bloch‐Zupan

Free

et al. 2006

American J of Med Genetics Pt B

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Axenfeld-Rieger Syndrome (ARS) is a genetically heterogeneous birth defect characterized by malformation of the anterior segment of the eye associated with glaucoma. Mutation of the PITX2 homeobox gene has been identified as a cause of ARS. We report a novel Arg5Trp missense mutation in the PITX2 homeodomain, which is associated with brain abnormalities. One patient had a small sella turcica likely to reflect hypoplasia of the pituitary gland and consistent with the critical role identified for Pitx2 in pituitary development in mice. Two patients had an enlarged cisterna magna, one with a malformed cerebellum, and two had executive skills deficits one in isolation and one in association with a below average intellectual capacity. The mutation caused a typical ARS ocular phenotype. All affected had iris hypoplasia, anterior iris to corneal adhesions, and corectopia. The ocular phenotype varied significantly in severity and showed some asymmetry. All affected also had redundant peri-umbilical skin, a hypoplastic maxilla, microdontia, and hypodontia missing between 20 and 27 teeth with an unusual pattern of tooth loss. Dental phenotypes were documented as they are often poorly characterized in ARS patients. All affected individuals showed an absence of first permanent molars with variable absence of other rarely absent teeth: the permanent upper central incisors, maxillary and mandibular first and second molars, and the mandibular canines. Based on the distinctive dental anomalies, we suggest that the dental phenotype can assist in predicting the presence of a PITX2 mutation and the possibility of brain abnormalities.

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Genetic Analysis of PITX2 and FOXC1 in Rieger Syndrome Patients From Brazil

Cited by 41 publications

References 4 publications

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Axenfeld-Rieger syndrome: new perspectives: Figure 1

A novel homeobox mutation in thePITX2gene in a family with Axenfeld‐Rieger syndrome associated with brain, ocular, and dental phenotypes

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