Novel Genetic Findings in a Chinese Family with Axenfeld-Rieger Syndrome

Li, Kuanshu; Liu, Yang; Liu, Ying; Ding, Lin

doi:10.1155/2017/5078079

Cited by 33 publications

(4 citation statements)

References 24 publications

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“…S6, A and B). The results indicate these alleles are polymorphic but not mutant, as described before (35). To evaluate their functions on regulating the expression of NKX2-5, we co-transfected H9c2 cells with different combinations of the expression plasmids of To confirm the activity of the polymorphic alleles of FOXC1 in regulating the expression of NKX2-5, we microinjected the mRNAs of the three FOXC1 alleles into zebrafish embryos at the 1-cell stage and then examined the endogenous expression of nkx2.5.…”

Section: The Foxc1 Mutants Identified From Ars Patients With Chd Display Different Activities Of Regulating the Nxk25 Expression In Zebrasupporting

confidence: 80%

Axenfeld-Rieger syndrome-associated mutants of the transcription factor FOXC1 abnormally regulate NKX2-5 in model zebrafish embryos

Zhang

Liu

Yue

et al. 2020

Journal of Biological Chemistry

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FOXC1 is a member of the forkhead family of transcription factors, and whose function is poorly understood. A variety of FOXC1 mutants have been identified in patients diagnosed with the autosomal dominant disease Axenfeld-Rieger syndrome, which is mainly characterized by abnormal development of the eyes, particularly those who also have accompanying congenital heart defects (CHD). However, the role of FOXC1 in CHD, and how these mutations might impact FOXC1 function, remains elusive. Our previous work provided one clue to possible function, demonstrating that zebrafish foxc1a, an orthologue of human FOXC1 essential for heart development, directly regulates the expression of nkx2.5, encoding a transcriptional regulator of cardiac progenitor cells. Abnormal expression of Nkx2-5 leads to CHD in mice and is also associated with CHD patients. Whether this link extends to the human system, however, requires investigation. In this study, we demonstrate that FOXC1 does regulate human NKX2-5 expression in a dose-dependent manner via direct binding to its proximal promoter. A comparison of FOXC1 mutant function in the rat cardiac cell line H9c2 and zebrafish embryos suggested that the zebrafish embryos might serve as a more representative model system than the H9c2 cells. Finally, we noted that three of the Axenfeld-Rieger syndrome FOXC1 mutations tested increased whereas a fourth repressed the expression of NKX2-5. These results imply that mutant FOXC1s might play etiological roles in CHD by abnormally regulating NKX2-5 in the patients. And zebrafish embryos can serve as a useful in vivo platform for rapidly evaluating disease-causing roles of mutated genes.

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Section: The Foxc1 Mutants Identified From Ars Patients With Chd Display Different Activities Of Regulating the Nxk25 Expression In Zebrasupporting

confidence: 80%

Axenfeld-Rieger syndrome-associated mutants of the transcription factor FOXC1 abnormally regulate NKX2-5 in model zebrafish embryos

Zhang

Liu

Yue

et al. 2020

Journal of Biological Chemistry

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“…To date, there have been few cases of FOXC1-associated ARS described in the Chinese population [13][14][15]. We report on one 5-year-old Chinese boy with hypertelorism, conductive hearing loss, dental defects and pupillary deformation, not the core features of ARS and identi ed heterozygosity for a de novo deletion in the FOXC1 gene by whole exome sequencing.…”

Section: Introductionmentioning

confidence: 93%

A Novel Variant in FOXC1 Associated With Atypical Axenfeld-Rieger Syndrome

Wang

Wang²,

Li³

et al. 2021

Preprint

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Background Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, therefore, clinical diagnosis present a huge challenge. Results In this study, we described a pathogenic variant in FOXC1 in one 5 year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linked to the FOXC1 variant and is coincidental. Conclusions Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

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“…In recent years, with the development of exome sequencing technology, genetic testing has gradually become a powerful tool for clinical diagnosis of this disease. Currently, five chromosomal loci associated with ARS have been identified, which are 4q25, 6p25, 11p13, 13q14, and 16q24, including PITX2 , FOXC1, PAX6, and FOXF1 genes [ 8 ]. About 40% of ARS cases have mutations in PITX2 and FOXC1 genes [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%