Haploinsufficiency of the <i>FOXA2</i> associated with a complex clinical phenotype

Mohammed, Idris; Al‐Khawaga, Sara; Bohanna, David; Shabani, A.; Khan, Faiyaz Ahmad; Love, Donald R.; Nawaz, Zafar; Hussain, Khalid

doi:10.1002/mgg3.1086

Cited by 6 publications

(3 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1 and S2). Ctr-iPSC lines showed normal karyotype, while FOXA2 +/− iPSC lines showed a translocation between the short arm of chromosome 6 and 20, karyotype: [46 XY, t (6; 20) (p11; p11)] and a deletion [46,XY,del (20) (p11.21p11.22)] as expected 24 and as reported in the patient sample 26 (Supplementary Fig. S1E).…”

Section: Derivation Of Ipscs From a Patient With Foxa2 Heterozygous Deletionsupporting

confidence: 65%

Aberrant development of pancreatic beta cells derived from human iPSCs with FOXA2 deficiency

et al. 2021

Self Cite

View full text Add to dashboard Cite

FOXA2 has been identified as an essential factor for pancreas development and emerging evidence supports an association between FOXA2 and diabetes. Although the role of FOXA2 during pancreatic development is well-studied in animal models, its role during human islet cell development remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from a patient with FOXA2 haploinsufficiency (FOXA2+/− iPSCs) followed by beta-cell differentiation to understand the role of FOXA2 during pancreatic beta-cell development. Our results showed that FOXA2 haploinsufficiency resulted in aberrant expression of genes essential for the differentiation and proper functioning of beta cells. At pancreatic progenitor (PP2) and endocrine progenitor (EPs) stages, transcriptome analysis showed downregulation in genes associated with pancreatic development and diabetes and upregulation in genes associated with nervous system development and WNT signaling pathway. Knockout of FOXA2 in control iPSCs (FOXA2−/− iPSCs) led to severe phenotypes in EPs and beta-cell stages. The expression of NGN3 and its downstream targets at EPs as well as INSUILIN and GLUCAGON at the beta-cell stage, were almost absent in the cells derived from FOXA2−/− iPSCs. These findings indicate that FOXA2 is crucial for human pancreatic endocrine development and its defect may lead to diabetes based on FOXA2 dosage.

show abstract

Section: Derivation Of Ipscs From a Patient With Foxa2 Heterozygous Deletionsupporting

confidence: 65%

Aberrant development of pancreatic beta cells derived from human iPSCs with FOXA2 deficiency

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Foxa2 +/– heterozygous mice fed a high-fat diet developed increased adiposity as a result of decreased energy expenditure ( 60 ). In humans, heterozygous deletions or point mutations of FOXA2 are associated with a genetic syndrome characterized by diverse organ defects, including pituitary abnormalities ( 61 – 63 ). Studies of human ECs have also raised the possibility that FOXA2 haploinsufficiency contributes to carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity

Sahoo¹,

Ramanand²,

Gao³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2’s role in EC is incompletely understood. Functional investigations using human and mouse EC cell lines revealed that FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. In live animals, conditional inactivation of Foxa2 or Pten alone in endometrial epithelium did not result in ECs, but simultaneous inactivation of both genes resulted in lethal ECs with complete penetrance, establishing potent synergism between Foxa2 and PI3K signaling. Studies in tumor-derived cell lines and organoids highlighted additional invasion and cell growth phenotypes associated with malignant transformation and identified key mediators, including Myc and Cdh1 . Transcriptome and cistrome analyses revealed that FOXA2 broadly controls gene expression programs through modification of enhancer activity in addition to regulating specific target genes, rationalizing its tumor suppressor functions. By integrating results from our cell lines, organoids, animal models, and patient data, our findings demonstrated that FOXA2 is an endometrial tumor suppressor associated with aggressive disease and with shared commonalities among its roles in endometrial function and carcinogenesis.

show abstract

“…10 Haploinsufficiency of the FOXA gene has been associated with multi-system as well as neuro-developmental disorders including ASD. 9 Therefore, detailed evaluation by pediatric surgeons is warranted if clinical features are indicative of possible Hirschsprung's disease.…”

Section: The Scale Of the Problem And Evolutionmentioning

confidence: 99%