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

Abstract

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.

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

“…Arg5 is involved both in DNA binding (without specificity) and in the nuclear localization signal. A mutation in PITX2 at the Arg5 position to tryptophan described in Axenfeld-Rieger syndrome (R43W) resulted in disruption of DNA binding and nuclear localization [Chi, 2005;Idrees et al, 2006]. In contrast, in our study, the nuclear localization of NKX2-1-p.R165W was not impaired in comparison to the wild-type protein.…”

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

“…Using this paradigm, we have demonstrated roles for the genes PAX6, PITX2, SOX2, OTX2 and RIMS1 in human brain development and cognitive function. [1][2][3][4] Mutations in PROM1 have been shown to result in retinitis pigmentosa, 5,6 macular degeneration 7,8 and cone-rod dystrophy. 9 PROM1 encodes prominin-1, a 5-transmembrane glycoprotein also known as CD133 and AC133.…”

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

“…These patients also respond poorly to medical or surgical pressure lowering interventions [Strungaru et al, 2007]. It is not uncommon for a single identified genetic mutation segregating within a family with AR to show variable phenotypic expression between different individuals [Honkanen et al, 2003;Idrees et al, 2006a;Komatireddy et al, 2003;Perveen et al, 2000]. For example, we have previously reported a single family with three affected individuals carrying an identical PITX2 mutation, exhibiting a range of phenotypes from iris hypoplasia and normal intraocular pressure to polycoria, corneal opacity, and glaucoma [Idrees et al, 2006a].…”