AimsTranscription factor GATA4 is a dosage sensitive regulator of heart development and alterations in its level or activity lead to congenital heart disease (CHD). GATA4 has also been implicated in cardiac regeneration and repair. GATA4 action involves combinatorial interaction with other cofactors such as NKX2-5, another critical cardiac regulator whose mutations also cause CHD. Despite its critical importance to the heart and its evolutionary conservation across species, the structural basis of the GATA4-NKX2-5 interaction remains incompletely understood.Methods and ResultsA homology model was constructed and used to identify surface amino acids important for the interaction of GATA4 and NKX2-5. These residues were subjected to site-directed mutagenesis, and the mutant proteins were characterized for their ability to bind DNA and to physically and functionally interact with NKX2-5. The studies identify 5 highly conserved amino acids in the second zinc finger (N272, R283, Q274, K299) and its C-terminal extension (R319) that are critical for physical and functional interaction with the third alpha helix of NKX2-5 homeodomain. Integration of the experimental data with computational modeling suggests that the structural arrangement of the zinc finger-homeodomain resembles the architecture of the conserved DNA binding domain of nuclear receptors.ConclusionsThe results provide novel insight into the structural basis for protein-protein interactions between two important classes of transcription factors. The model proposed will help to elucidate the molecular basis for disease causing mutations in GATA4 and NKX2-5 and may be relevant to other members of the GATA and NK classes of transcription factors.
BackgroundIn the developed countries, uveal melanoma is the most common primary intraocular malignancy in adults. Little is known about the epidemiological and geographical distribution of uveal melanoma in Canada.MethodsTo determine the incidence patterns and geographical distribution of uveal melanoma cases in Canada, we conducted the first comprehensive, population-based national study of this malignancy across all Canadian provinces and territories during 1992–2010 years. We examined two independent population-based registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer using corresponding International Classification of Diseases for Oncology-3rd edition codes for all histological subtypes of uveal melanoma.ResultsWe report that 2215 patients were diagnosed with uveal melanoma, of which 52.1% were males. The average -annual incidence rate of uveal melanoma in Canada was 3.75 cases per million individuals per year (95% CI 3.60 to 3.91). Overall, we report a steady increase in uveal melanoma incidence with an annual increase of 0.074 cases per million individuals per year. Significant differences in the incidence rates of uveal melanoma between Canadian provinces and territories were noted, where the highest crude incidence was in British Columbia and Saskatchewan with rates of 6.38 and 5.47 cases per million individuals per year, respectively.ConclusionsThis work, for the first time, defines the disease burden of uveal melanoma in Canada and highlights important longitudinal, geographical and spatial differences in the distribution of uveal melanoma in Canada.
TBX5, a member of the T-box family of transcription factors, is a dosage sensitive regulator of heart development. Mutations in TBX5 are responsible for Holt-Oram Syndrome, an autosomal dominant disease with variable and partially penetrant cardiac defects suggestive of the existence of genetic and environmental modifiers. KLF13, a member of the Krüppel-like family of zinc finger proteins is co-expressed with TBX5 in several cardiac cells including atrial cardiomyocytes and cells of the interatrial septum. We report that KLF13 interacts physically and functionally with TBX5 to synergistically activate transcription of cardiac genes. We show that TBX5 contacts KLF13 via its T-domain and find that several disease-causing mutations therein have decreased KLF13 interaction. Whereas Klf13 heterozygote mice have no detectable cardiac defects, loss of a Klf13 allele in Tbx5 heterozygote mice significantly increases the penetrance of TBX5-dependent cardiac abnormalities including atrial, atrial-ventricular and ventricular septal defects. The results reveal for the first time combinatorial interaction between a T-box protein and a KLF family member and its importance for heart and possibly other organ development. The data also suggest that, in human, KLF13 may be a genetic modifier of the Holt-Oram Syndrome gene TBX5.
BackgroundMelanoma is the most common primary malignancy of the eye in adults. While the epidemiology of uveal melanoma has recently been described in Canada, little is known about the epidemiology and geographic distribution of patients with conjunctival melanoma (CM) in Canada.MethodsWe conducted a population-based study of CM incidence across all Canadian provinces and territories during 1992–2010 using two independent population-based registries.Results190 patients were diagnosed with CM in Canada from 1992 to 2010. 55.3 % of these patients were men. The mean annual incidence rate of CM in Canada was 0.32 cases per million individuals (0.35 and 0.29 cases per million individuals for men and women, respectively). The incidence rates for Canadian provinces demonstrated that the eastern provinces of Nova Scotia and New Brunswick had higher age-adjusted incidence rates than the national average, with rates of 0.52 and 0.47 cases per million individuals per year, respectively.ConclusionsThis analysis demonstrates novel variations in CM incidence rates between different Canadian provinces. These results taken together with the data reported from the USA confirm the North-to-South geographic gradient of increasing CM incidence. This research highlights that the epidemiology of CM in North America is comparable to that of cutaneous malignant melanoma in contrast to the trends for uveal melanoma distribution.
Purpose: To determine the incidence rates and geographic distribution of retinoblastoma in Canada to aid cancer control programs. Methods: Patients with retinoblastoma whose data were available from the Canadian Cancer Registry (CCR) and Le Registre Québécois du Cancer (LRQC) were studied. Using third edition International Classification of Diseases for Oncology (ICD-O) codes, the authors examined the incidence rates and geographic distribution of patients with retinoblastoma between 1992 and 2010. Patient data including sex, age, and laterality of the retinoblastoma were analyzed. Results: Between 1992 and 2010 in Canada, the average annual incidence rate of retinoblastoma was 11.58 cases per 1 million children younger than 5 years (95% CI [confidence interval]: 10.48 to 12.76). The incidence rate was stable over time, with an average age at diagnosis of 2.30 ± 6.85 years and no gender predilection. The laterality of the reported cases was 81.48% for uni-lateral cases and 18.52% for bilateral cases. Provincially, Nova Scotia had twice the national average and the highest incidence rates of retinoblastoma across the Canadian provinces. Conclusions: This is the first study to define the disease burden of retinoblastoma and to highlight important longitudinal, geographic, and spatial differences in the distribution of retinoblastoma in Canada between 1992 and 2010. The results of this study indicate continuity of clinical trends between Canada, the United States, and other developed countries. [ J Pediatr Ophthalmol Strabismus . 2019;56(2):124–130.]
BackgroundOphthalmic lymphoma (OL) is the most common orbital tumour, particularly in older individuals. Little is known about the epidemiology and geographic distribution of OL in Canada. Descriptive demographic statistics are an important first step in understanding OL burden and are necessary to inform comprehensive national cancer prevention programmes.MethodsWe determined patterns of incidence and geographical distribution of the three major subtypes of OL: extranodal marginal zone B cell lymphoma, follicular lymphoma (FL) and diffuse large B cell lymphoma. Here, we used cases that were diagnosed during 1992–2010 using two independent population-based cancer registries, the Canadian Cancer Registry and Le Registre Québécois du Cancer (LRQC).ResultsThe OL mean annual age-standardised incidence rate for 1992–2010 was 0.65 cases per million people per year with an average annual increase in the incidence rate of 4.5% per year. The mean age of diagnosis was 65 years. OL incidence rate was the highest in the cities located along the heavily industrialised Strait of Georgia in British Columbia.ConclusionsOur data on patient age, sex and temporal trends showed similarities with data reported in the USA and Denmark. Additional studies are needed to determine whether the observed increase in OL incidence is genuine or spurious.
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