CUGC for posterior polymorphous corneal dystrophy (PPCD)

Davidson, Alice E.; Hafford-Tear, Nathaniel J.; Ďuďáková, Ľubica; Sadan, Amanda N; Pontikos, Nikolas; Hardcastle, Alison J.; Tuft, Stephen; Lišková, Petra

doi:10.1038/s41431-019-0448-8

Cited by 5 publications

(1 citation statement)

References 15 publications

(43 reference statements)

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“…Several variants in non-coding gene promoter and regulatory elements regions have been identified in genetic diseases. The majority of them mediates their regulatory effects through alteration of transcriptional factors binding and disturb trans-activation of the target gene promoter [18][19][20][21]. Promoter mutations have also been identified in cancer predisposition genes, like in the alternative promoter of APC that disrupts the binding of YY1 and reduces APC 1B promoter activity in human gastric cell lines [22].…”

Section: Introductionmentioning

confidence: 99%

Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence

et al. 2022

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Purpose: X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the Xlinked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression.Methods: Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells.Results: NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression.Conclusions: These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

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