The relationship between RANBP2 and Leigh syndrome spectrum (LSS) was evaluated using the ClinGen Clinical Validity Framework as of August 17, 2020. The RANBP2 gene encodes RAN-binding protein 2, a nuclear pore complex component that has been annotated as an E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. The nuclear pore complex spans the nuclear envelope and allows the flow of molecules (proteins, RNA, carbohydrates, lipids and signaling molecules) between the nucleus and cytoplasm.
The RANBP2 gene was first reported in relation to autosomal dominant Leigh syndrome spectrum in 2015 (PMID: 26110162). Pathogenic variants in RANBP2 are more commonly associated with acute necrotizing encephalopathy (ANE), however biochemical testing is typically not pursued in these cases as features arise in the setting of a viral illness. Indeed, RANBP2-related disorders are thought to arise due to a combination of a genetic and viral insult. Furthermore, ANE has distinctive histopathological and imaging features, with lesions that may affect the basal ganglia, brainstem, and, most frequently, the thalamus. Therefore, imaging studies may prompt/indicate a potential overlap with the diagnosis of LSS. However, unlike lesions in LSS, the core of the lesions associated with ANE, particularly those in the thalamus, are usually composed of significant perivascular hemorrhage and necrosis of neurons and glial cells. Evidence supporting the gene-disease relationship between RANBP2 and LSS includes case-level data and experimental data. This curation included one variant identified in one case in one publication (PMID: 26110162). No segregation data were available. The exact mechanism of disease is uncertain. This gene-disease association is also supported by expression data and functional alteration in non-patient cells (PMIDs: 18853439, 17887960).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 17, 2020 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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