Biomedical subjects

Matthew A Lines

Publications and source records attributed to Matthew A Lines.

5 recordsLinked to original sources

PubMed2006

Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis.

Axenfeld-Rieger ocular dysgenesis is associated with mutations of the human PITX2 and FOXC1 genes, which encode transcription factors of the homeodomain and forkhead types, respectively. We have identified a functional link between FOXC1 and PITX2 which we propose underpins the similar Axenfeld-Rieger phenotype caused by mutations of these genes. FOXC1 and PITX2A physically interact, and this interaction requires crucial functional domains on both proteins: the C-terminal activation domain of FOXC1 and the homeodomain of PITX2. Immunofluorescence further shows PITX2A and FOXC1 to be colocalized within a common nuclear subcompartment. Furthermore, PITX2A can function as a negative regulator of FOXC1 transactivity. This work ties both proteins into a common pathway and offers an explanation of why increased FOXC1 gene dosage produces a phenotype resembling that of PITX2 deletions and mutations. Ocular phenotypes arise despite the deregulated expression of FOXC1-target genes through mutations in FOXC1 or PITX2. Ultimately, PITX2 loss of function mutations have a compound effect: the reduced expression of PITX2-target genes coupled with the extensive activation of FOXC1-regulated targets. Our findings indicate that the functional interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and related anterior segment dysgeneses.

Animals↗

PubMed2004

Genetics and ARMD.

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ATP-Binding Cassette Transporters↗

PubMed2004

Characterization and prevalence of PITX2 microdeletions and mutations in Axenfeld-Rieger malformations.

PURPOSE: Mutations of the homeodomain protein PITX2 produce Axenfeld-Rieger (AR) malformations of the anterior chamber, an autosomal dominant disorder accompanied by a 50% risk of glaucoma. Twenty-nine mutations of PITX2 have been described, with a mutational prevalence estimated between 10% and 60% in AR. In the current study, the possible role of altered PITX2 gene dosage in the etiology of AR was investigated. Gross gene deletions and duplications should alter PITX2 activity analogously to hypomorphic and hypermorphic mutations, respectively. METHODS: Sixty-four patients with AR, iridogoniodysgenesis (IGD), iris hypoplasia (IH), or anterior segment dysgenesis (ASD) were screened for PITX2 mutations by sequencing. PITX2 gene dosage was concurrently examined in these patients by real-time quantitative PCR. Microsatellite markers were used to map 4q25 microdeletions at a contig scale, as well as for haplotype analysis in an extended AR kindred. An additional 27 patients with other assorted ocular phenotypes were evaluated by similar methods, amounting to a total of 91 cases analyzed. RESULTS: Three novel mutations of PITX2 (4.7%) were identified among 64 patients with AR, IGD, IH, or ASD. Deletions of PITX2 were as frequent as mutations in our sample. Chromosome 4q25 microdeletions were physically mapped relative to several microsatellite markers in each patient. Cosegregation of AR and a PITX2 deletion was demonstrated in an extended kindred. CONCLUSIONS: Point mutations and gross deletions of PITX2 appear to produce an equivalent haploinsufficiency phenotype. Quantitative PCR is an efficient means of detecting causative PITX2 deletions in patients with AR and may increase the detection rate at this locus.

Anterior Eye Segment↗

PubMed2002

Molecular genetics of Axenfeld-Rieger malformations.

Axenfeld-Rieger (AR) malformations are autosomal dominant developmental defects of the anterior segment of the eye, and often result in glaucomatous blindness. AR malformations are associated with mutations in two transcription factor genes (PITX2 and FOXC1) expressed throughout eye ontogeny. Studies of disease-associated mutant proteins have provided insights into the aetiology of AR malformations, while delineating residues and domains important to DNA binding, transactivation and nuclear localization. The availability of mouse models for both PITX2 and FOXC1 has allowed detailed study of their expression and mutant phenotypes. Dissection of the normal functions and domain structures of these factors will aid in future elucidation of how alterations of the developmental program produce the dysgenic phenotypes seen in AR. There are at least two AR loci still awaiting molecular cloning on chromosomes 13q14 and 16q24. Identification of further genes implicated in aberrations of human ocular development will advance our understanding of the mechanisms whereby pattern is established in the eye, and may be of clinical value in treating the glaucoma that is the most serious consequence of AR malformations.

Abnormalities, Multiple↗

PubMed2002

Electrophysiologic and phenotypic features of an autosomal cone-rod dystrophy caused by a novel CRX mutation.

PURPOSE: To reexamine a large Albertan family previously reported with a progressive cone dystrophy with variable phenotype and to map the disorder using molecular genetic techniques. DESIGN: Observational case series. PARTICIPANTS: Twenty-nine subjects (10 affected) from four generations of a large kindred were clinically examined. Twenty-three of these individuals, as well as two unaffected spouses, were included in the molecular genetic study. Subject ages ranged from 17 to 91 years of age. METHODS: Disease status and associated ocular abnormalities were assessed primarily by measurement of visual acuity, color vision, fundus photography, and both full-field and multifocal electroretinography (ERG and mfERG). Linkage of the disorder to the rhodopsin gene was studied using microsatellites. A mutational screen of the CRX gene was performed to identify coding sequence changes. MAIN OUTCOME MEASURES: Visual acuity and color discrimination were reduced in clinically affected individuals; full-field flash ERG was used to measure function of both cones and rods. mfERG and fundus photography allowed documentation of the observed macular changes. RESULTS: We noted a variable, adult-onset macular dystrophy, progressing in some cases to a retinitis pigmentosa-like phenotype. Both photopic and scotopic full-field ERG amplitudes were reduced by approximately 50%, demonstrating involvement of both photoreceptor systems. A reduced b-wave amplitude with a relatively preserved a-wave was observed at both cone and rod levels. Macular involvement was confirmed by mfERG. The rhodopsin locus was excluded by haplotype analysis. A novel frameshift mutation was detected in exon III of the CRX retinal homeobox gene. ERG and molecular genetic findings were consistent with the reclassification of this disease as an autosomal dominant cone-rod dystrophy (CRD) CONCLUSIONS: We report a novel CRX mutation causing autosomal dominant CRD. Observed ERG changes suggest that this mutation primarily impairs inner retinal function. Because retinal expression of CRX is limited to photoreceptors, this dysfunction may be the result of faulty photoreceptor communication with second-order retinal neurons. We propose misexpression of gated cation channels caused by altered CRX activity as one putative mechanism by which a sole photoreceptor defect may selectively impair neurotransmission without disrupting the upstream events of phototransduction.

Adolescent↗