RNF31 (also known as HOIP) was first reported in relation to autosomal recessive immunodeficiency 115 with autoinflammation in 2015 (Boisson et al., PMID 2600889). This condition is also referred to as HOIP deficiency in the literature. HOIP deficiency is characterized by combined immunodeficiency (impaired B cell and T cell lymphocyte function), recurrent bacterial, fungal, and viral infections, abnormal immunoglobulin levels, splenomegaly, systemic inflammation, particularly of the joints, systemic lymphangiectasia, antibody deficiency particularly after vaccination, impaired bone development, and a single case of necrotizing lymphadenitis. At least 4 unique variants (2 missense, 1 frameshift, and 1 intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Variants in this gene have been reported in at least 3 unrelated probands in 2 publications (PMID 2600889, 30936877, 39009172). There was no evidence of phenotype in heterozygous carriers. The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease relationship is supported by expression studies, animal models, in vitro functional assays, protein interactions, and rescue in patient derived cells (PMID 26008899, 30936877, 32543267, 33215740, 38582895). RNF31 was demonstrated to interact with SHARPIN and RBCK1, to form the LUBAC complex which is responsible for regulation of the NF-κB pathway through linear ubiquitin chain formation. Disruption to RNF31 protein function showed impaired autophagy processes, presence of inflammatory markers in patient and animal model cells, instability of the LUBAC complex, and susceptibility to infection. Animal models partially recapitulated the phenotype observed in individuals.
In summary, there is moderate evidence to support this gene-disease relationship. This classification was approved by the ClinGen SCID/CID Gene Curation Expert Panel on 7/18/2024 (SOP Version [11]).
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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