TOPBP1 (topoisomerase IIβ-binding protein 1 ) encodes protein which is involved in DNA replication, especially in DNA damage repair (PMID:20012580). TOPBP1 was first suggested in connection with autosomal dominant PAH in 2014 after 3 variants (rs55633281, rs17301766 and rs10935070) were identified in a cohort of 12 IPAH patients (Perez et al., PMID: 24702692). These variants are common (allele frequency >5% in multiple populations), and therefore were not scored as a part of this curation. There have been other case-control studies performed, all of which do not show a significant difference in the frequency of the previously mentioned TOPBP1 variants (PMID:30084161) or other rare variants (PMID:29650961) between PAH patients and controls. Functionally, expression of TOPBP1 was shown to be reduced in PAH patient cells. Furthermore, siRNA knockdown of TOPB1 in control cells resulted in altered tube formation in PMVECs (pulmonary microvascular endothelial cells) in vitro. Subsequently, overexpression of TOPBP1 rescued the tube malformations in PAH patient PMVECs (PMID:24702692).
In summary, due to. the. lack. of genetic. evidence, TOPBP1 has no known disease relationship with autosomal dominant PAH. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on the meeting date 8/30/22 (SOP Version 9).
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