Abstract: SA-PO416
Variants in the Bidirectional Promoter of GLA and HNRNPH2 Associated with Fabry Disease
Session Information
- Genetic Diseases of the Kidney - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Al-Obaide, Mohammed A., Texas Tech University Health Sciences Center, Amarillo, Texas, United States
- Vasylyeva, Tetyana L., Texas Tech University Health Sciences Center, Amarillo, Texas, United States
Background
Heterogeneous clinical presentation of Fabry disease is not yet completely understood. Although, heterozygous Fabry females generally show an attenuated form of Fabry disease; in some cases, they show a severe phenotype. A severe case of heterozygous female (HF) was attributed to CpG Island (CGI) methylation specifically at mutation site c.36C>A in the GLA gene exon 1, the patient's non-mutated allele C, which is prone to methylation, remained unchanged [Mol Genet Metab (2017) 120(3):173-179]. Even though the status of the CGI methylation in silencing genes’ expressions is divisive, the overall view is that methylation can repress transcription factor binding. Genomic databases show overlapping sequence at 5-prime sides of GLA and HNRNPH2 divergently paired loci. Mutations at the upstream of HNRNPH2 sequence can cause Fabry disease. We aimed to investigate the molecular features of GLA and HNRNPH2 predicted bidirectional promoter that control the expression of the two divergently paired genes and their association with Fabry disease.
Methods
Genomic databases and prediction tools for promoters, transcription factor binding sites and CGI were used to identify and analyze the intervening sequence for GLA and HNRNPH2 and the bidirectional promoter.
Results
Most bidirectional promoters are GC rich and exhibit CGIs prone to methylation, and characterized by five transcription factors binding sites (TFSBSs) (GABPA/NRF2, NRF1, NFY, YY1, and ZNF143). The predicted GLA and HNRNHP2 bidirectional promoter sequence located at chrX: 101,407,191-101,409,040 on the reverse strand composed of 1850 bps. We identified 831 bps intervening sequence for GLA and HNRNHP2-reverse complement. The five specific TFBSs were identified and marked along the predicted bidirectional promoter sequence. The lengths of four identified CGIs were between 100 and 323 bases. The criteria used for identification of CGI were: CGI size > 100, %G+%C Percent > 50.0, Obs/Exp CpG ratio > 0.6). Intriguingly, the c.36C>A variant of HF patient was mapped at NRF1 motif identified by our bioinformatic analysis. Methylation reduced binding of NRF1 transcription factor to those sites [Cell Rep (2017) 19(11):2383-2395].
Conclusion
The molecular characteristics of identified GLA and HNRNHP2 bidirectional promoter define the role of upstream variants of the divergently paired GLA and HNRNPH2 genes in Fabry disease.
Funding
- Commercial Support –