The SAT1 gene encodes diamine acetyltransferase 1, a rate-limiting enzyme that catalyzes the acetylation of polyamines and is involved in the conversion of spermidine and spermine to putrescine (PMIDs: 8500690, 27698118). SAT1 was first reported in relation to X-linked recessive pediatric systemic lupus erythematosus (SLE) in 2022 (Xu et al., PMID: 35977808).
Genetic evidence reviewed in the curation of this gene-disease relationship included 2 hemizygous variants (p.Asp40Tyr and p.Glu92Leufs*6) identified in 4 males diagnosed with childhood-onset SLE (PMID: 35977808). The mechanism of pathogenicity appears to be loss of function.
The gene-disease relationship is also supported by experimental evidence. A knock-in mouse model in which both hemizygous male and homozygous female mice carry the p.Glu92Leufs*6 frameshift variant in Sat1 develops pathologies resembling SLE (PMID: 35977808). Functional alteration assays using neutrophils isolated from the mouse model show that the p.Glu92Leufs*6 variant causes spontaneous NETosis and autophagy defects (PMID: 35977808). Decreased plasma levels of spermidine and spermine are observed in SLE populations as compared to healthy controls (PMIDs: 29308729, 35977808).
In summary, there is limited evidence to support the relationship between SAT1 and pediatric systemic lupus erythematosus. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date June 14, 2024 (SOP Version 10).
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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