SAT1

protein-coding

spermidine/spermine N1-acetyltransferase 1, the group of GCN5 related N-acetyltransferases

Gene summary

The protein encoded by this gene belongs to the acetyltransferase family, and is a rate-limiting enzyme in the catabolic pathway of polyamine metabolism. It catalyzes the acetylation of spermidine and spermine, and is involved in the regulation of the intracellular concentration of polyamines and their transport out of cells. Defects in this gene are associated with keratosis follicularis spinulosa decalvans (KFSD). Alternatively spliced transcripts have been found for this gene.[provided by RefSeq, Sep 2009]

Previous symbols:

MANE transcript

NM_002970.4

Inheritance

ClinVar variants

U:33B:3

Top phenotype

systemic lupus erythematosus

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:23,783,173-23,786,210

External References & Databases

Ensembl (ENSG00000130066)

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic lupus erythematosusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0007915

Submitter: PanelApp Australia

pediatric systemic lupus erythematosusLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0019725

Submitter: ClinGen

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).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SAT1 variants in ClinVar

2 Conditions Cataloged

not providedTotal: 4

not specifiedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002970.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	1 clinvar		5
missense			12 clinvar	2 clinvar		14
nonsense			3 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			14 clinvar			14
Total	0	0	33	3	0	36

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002970.4	RefSeq	NP_002961.1	6	MANE Select
ENST00000379270.5	Ensembl	ENSP00000368572.4	6	MANE Select
ENST00000379254.5	Ensembl	ENSP00000368556.1	5	Standard
ENST00000379254.6	Ensembl	ENSP00000368556.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sat1b	Danio rerio	Structure: intersegmental vessel Quality: decreased functionality abnormal

Gene / Model

Organism

Observed Phenotype

sat1b

Danio rerio

Structure: intersegmental vessel

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Ferroptosis - Homo sapiens (human)
NOTCH1 regulation of human endothelial cell calcification
Nucleotide Metabolism
Interconversion of polyamines

Biological Process

angiogenesis
polyamine biosynthetic process
putrescine catabolic process
spermidine acetylation
regulation of cell population proliferation

Molecular Function

diamine N-acetyltransferase activity
protein binding
N-acetyltransferase activity
spermidine binding
identical protein binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379270
Coding exons: 6
Length: 3054
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125714
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.71	25	63.1	0.396	0.00000443	1137
Missense (PolyPhen)		4	16.583	0.24121		298
Synonymous	-2.17	37	23.6	1.57	0.00000179	293
Loss of Function	2.40	0	6.68	0.00	4.22e-7	132

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Enzyme which catalyzes the acetylation of polyamines. Substrate specificity: norspermidine = spermidine >> spermine > N(1)-acetylspermine > putrescine. This highly regulated enzyme allows a fine attenuation of the intracellular concentration of polyamines. Also involved in the regulation of polyamine transport out of cells. Acts on 1,3-diaminopropane, 1,5-diaminopentane, putrescine, spermidine (forming N(1)- and N(8)-acetylspermidine), spermine, N(1)-acetylspermidine and N(8)-acetylspermidine. {ECO:0000269|PubMed:16455797, ECO:0000269|PubMed:17516632}.;
Disease: DISEASE: Keratosis follicularis spinulosa decalvans X-linked (KFSDX) [MIM:308800]: A rare disorder affecting the skin and the eye. Affected men show thickening of the skin of the neck, ears, and extremities, especially the palms and soles, loss of eyebrows, eyelashes and beard, thickening of the eyelids with blepharitis and ectropion, and corneal degeneration. {ECO:0000269|PubMed:12215835, ECO:0000269|PubMed:9341865}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0945

Intolerance Scores

RVIS EVS: -0.03
RVIS percentile EVS: 51.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.969

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium