FASTKD3

Summary

FASTKD3 (FAST kinase domains 3, HGNC:28758) is a protein-coding gene on chromosome 5p15.31, encoding FAST kinase domain-containing protein 3, mitochondrial (Q14CZ7). Required for normal mitochondrial respiration.

This gene encodes a member of a small family of Fas-activated serine/threonine kinase domain (FASTKD) containing proteins that share an amino terminal mitochondrial targeting domain and multiple carboxy terminal FAST domains as well as a putative RNA-binding RAP domain. The members of this family are ubiquitously expressed and are generally most abundant in mitochondria-enriched tissues such as heart, skeletal muscle and brown-adipose tissue. Some members of this protein family may play a role in apoptosis. The protein encoded by this gene interacts with components of the mitochondrial respiratory and translation networks. A pseudogene of this gene is also present on chromosome 5. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 79072 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_024091

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28758
Approved symbol	FASTKD3
Name	FAST kinase domains 3
Location	5p15.31
Locus type	gene with protein product
Status	Approved
Aliases	MGC5297, FLJ23274
Ensembl gene	ENSG00000124279
Ensembl biotype	protein_coding
OMIM	617530
Entrez	79072

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000264669, ENST00000282110, ENST00000504695, ENST00000507036, ENST00000507572, ENST00000511261, ENST00000513577, ENST00000513658, ENST00000870229, ENST00000966723

RefSeq mRNA: 1 — MANE Select: NM_024091 NM_024091

CCDS: CCDS3873

Canonical transcript exons

ENST00000264669 — 7 exons

Exon	Start	End
ENSE00001130855	7866646	7868196
ENSE00001430975	7868979	7869031
ENSE00001912408	7859159	7859539
ENSE00003475392	7861149	7861263
ENSE00003480766	7861583	7861652
ENSE00003563585	7865898	7865983
ENSE00003671756	7862823	7862997

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 93.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.8847 / max 111.9375, expressed in 1787 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60868	10.5711	1787
60867	0.3137	94

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	93.15	gold quality
secondary oocyte	CL:0000655	92.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.24	gold quality
jejunal mucosa	UBERON:0000399	88.26	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.87	gold quality
right uterine tube	UBERON:0001302	87.51	gold quality
nephron tubule	UBERON:0001231	87.23	gold quality
colonic mucosa	UBERON:0000317	86.43	gold quality
biceps brachii	UBERON:0001507	86.28	gold quality
hair follicle	UBERON:0002073	86.27	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.20	gold quality
metanephros cortex	UBERON:0010533	85.86	gold quality
right adrenal gland cortex	UBERON:0035827	85.50	gold quality
tibia	UBERON:0000979	85.48	gold quality
palpebral conjunctiva	UBERON:0001812	85.44	gold quality
right adrenal gland	UBERON:0001233	85.24	gold quality
mucosa of transverse colon	UBERON:0004991	84.89	gold quality
left adrenal gland	UBERON:0001234	84.81	gold quality
ventricular zone	UBERON:0003053	84.56	gold quality
calcaneal tendon	UBERON:0003701	84.54	gold quality
gingival epithelium	UBERON:0001949	84.50	gold quality
cortex of kidney	UBERON:0001225	84.46	gold quality
metanephros	UBERON:0000081	84.37	gold quality
left adrenal gland cortex	UBERON:0035825	84.31	gold quality
nasal cavity mucosa	UBERON:0001826	84.28	gold quality
rectum	UBERON:0001052	84.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.19	gold quality
germinal epithelium of ovary	UBERON:0001304	84.09	gold quality
duodenum	UBERON:0002114	84.03	gold quality
adrenal cortex	UBERON:0001235	84.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting FASTKD3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-3117-5P	99.04	67.93	618
HSA-MIR-1288-5P	98.85	67.01	734

Literature-anchored findings (GeneRIF, showing 3)

• these results introduce FASTKD3 as an essential component of mitochondrial respiration that may modulate energy balance in cells exposed to adverse conditions by functionally coupling mitochondrial protein synthesis to respiration. (PMID:20869947)
• FASTKD3 is required for efficient COX1 mRNA translation without altering mRNA levels, which results in a decrease in the steady-state levels of COX1 protein. (PMID:27789713)
• Despite the fact that proteins of the FASTK family FASTKD1-5 share the same domains, they exhibit various-sometimes opposing-functions in almost all steps of mitochondrial RNA metabolism. (PMID:29036396)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fastkd3	ENSDARG00000100440
mus_musculus	Fastkd3	ENSMUSG00000021532
rattus_norvegicus	Fastkd3	ENSRNOG00000027422

Paralogs (5): FASTKD2 (ENSG00000118246), TBRG4 (ENSG00000136270), FASTKD1 (ENSG00000138399), FASTK (ENSG00000164896), FASTKD5 (ENSG00000215251)

Protein

Protein identifiers

FAST kinase domain-containing protein 3, mitochondrial — Q14CZ7 (reviewed: Q14CZ7)

All UniProt accessions (5): D6RAR6, D6RB04, D6RC07, D6RHY4, Q14CZ7

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal mitochondrial respiration. Increases steady-state levels and half-lives of a subset of mature mitochondrial mRNAs MT-ND2, MT-ND3, MT-CYTB, MT-CO2, and MT-ATP8/6. Promotes MT-CO1 mRNA translation and increases mitochondrial complex IV assembly and activity.

Subcellular location. Mitochondrion.

Tissue specificity. Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in liver and thyroid.

Domain organisation. RAP domain is required for FASTKD3 function in mRNA stability and translation.

Similarity. Belongs to the FAST kinase family.

RefSeq proteins (1): NP_076996* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010622	FAST_Leu-rich	Domain
IPR013579	FAST_2	Domain
IPR013584	RAP	Domain
IPR050870	FAST_kinase	Family

Pfam: PF06743, PF08368, PF08373

UniProt features (7 total): sequence variant 4, transit peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14CZ7-F1	81.59	0.59

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 112 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS

GO Biological Process (4): mitochondrial RNA processing (GO:0000963), mitochondrial respiratory chain complex IV assembly (GO:0033617), regulation of mitochondrial mRNA stability (GO:0044528), positive regulation of mitochondrial translation (GO:0070131)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), ribonucleoprotein granule (GO:0035770)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
mitochondrial RNA metabolic process	1
RNA processing	1
mitochondrial gene expression	1
respiratory chain complex IV assembly	1
mitochondrial respiratory chain complex assembly	1
regulation of mRNA stability	1
mitochondrial translation	1
positive regulation of translation	1
regulation of mitochondrial translation	1
nucleic acid binding	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
intracellular membraneless organelle	1
supramolecular complex	1

Protein interactions and networks

STRING

2066 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FASTKD3	PTCD1	O75127	802
FASTKD3	DHX30	Q7L2E3	670
FASTKD3	MRPS31	Q92665	651
FASTKD3	PNPT1	Q8TCS8	621
FASTKD3	IARS2	Q9NSE4	608
FASTKD3	MTO1	Q9Y2Z2	602
FASTKD3	LRPPRC	P42704	600
FASTKD3	MRPS22	P82650	599
FASTKD3	GFM1	Q96RP9	589
FASTKD3	MTRR	Q9UBK8	558
FASTKD3	FASTKD2	Q9NYY8	538
FASTKD3	TUFM	P49411	533
FASTKD3	AMZ1	Q400G9	512
FASTKD3	TARS2	Q9BW92	505
FASTKD3	CCDC57	Q2TAC2	491

IntAct

55 interactions, top by confidence:

A	B	Type	Score
FAM9B	FASTKD3	psi-mi:“MI:0915”(physical association)	0.670
FASTKD3	FAM9B	psi-mi:“MI:0915”(physical association)	0.670
FASTKD3	MAGEA12	psi-mi:“MI:0915”(physical association)	0.560
FASTKD3	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
AGTRAP	FASTKD3	psi-mi:“MI:0915”(physical association)	0.560
MAGEA12	FASTKD3	psi-mi:“MI:0915”(physical association)	0.560
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
SPACA1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
steC	SCD	psi-mi:“MI:0914”(association)	0.460
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
BSG	METTL15	psi-mi:“MI:0914”(association)	0.350
SLAMF1	RTCA	psi-mi:“MI:0914”(association)	0.350
VTN	HAT1	psi-mi:“MI:0914”(association)	0.350
MUC20	RAD51B	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
SPACA1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (149): FASTKD3 (Two-hybrid), FASTKD3 (Two-hybrid), FAM9B (Two-hybrid), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS), FASTKD3 (Affinity Capture-MS)

ESM2 similar proteins: A1A5P5, A1L2L5, A1Z9A8, B5DF07, O15091, P42704, Q07DV3, Q08CK1, Q0IHP3, Q14C51, Q14CX7, Q14CZ7, Q28C74, Q28DE0, Q2KI62, Q32LU7, Q32N55, Q32PI8, Q3SZ55, Q4R366, Q4R6I5, Q53R41, Q566X6, Q58CX2, Q5R503, Q5R8W8, Q5RFI6, Q5SGE0, Q5XIR8, Q5ZKK3, Q5ZLS8, Q68FN9, Q6AYP3, Q6DI86, Q6GQ66, Q6PB66, Q6QI44, Q7L8L6, Q7TMV3, Q7Z3E5

Diamond homologs: Q14CZ7, Q58CX2, Q68FN9, Q8BSN9, Q5M7V7, Q5R776, Q922E6, Q9NYY8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

87 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	13
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

756 predictions. Top by Δscore:

Variant	Effect	Δscore
5:7861143:CCGTA:C	donor_loss	1.0000
5:7861144:CGTA:C	donor_loss	1.0000
5:7861145:GTACC:G	donor_loss	1.0000
5:7861146:TACC:T	donor_loss	1.0000
5:7861147:A:AT	donor_loss	1.0000
5:7861159:TGATA:T	donor_gain	1.0000
5:7861259:CTATC:C	acceptor_gain	1.0000
5:7861260:TATC:T	acceptor_gain	1.0000
5:7861261:ATC:A	acceptor_gain	1.0000
5:7861262:TC:T	acceptor_gain	1.0000
5:7861263:CC:C	acceptor_gain	1.0000
5:7861264:C:CC	acceptor_gain	1.0000
5:7859538:ATC:A	acceptor_loss	0.9900
5:7859540:C:CA	acceptor_loss	0.9900
5:7859540:C:CC	acceptor_gain	0.9900
5:7861147:A:AC	donor_gain	0.9900
5:7861148:C:CC	donor_gain	0.9900
5:7861264:C:T	acceptor_gain	0.9900
5:7861271:A:AC	acceptor_gain	0.9900
5:7861271:A:C	acceptor_gain	0.9900
5:7861577:CTGTA:C	donor_loss	0.9900
5:7861578:TGTAC:T	donor_loss	0.9900
5:7861579:GTACC:G	donor_loss	0.9900
5:7861580:TA:T	donor_loss	0.9900
5:7861582:CCT:C	donor_loss	0.9900
5:7861650:CAT:C	acceptor_gain	0.9900
5:7861650:CATCT:C	acceptor_loss	0.9800
5:7861652:TCTGG:T	acceptor_loss	0.9800
5:7861653:C:T	acceptor_loss	0.9800
5:7859537:GAT:G	acceptor_gain	0.9700

AlphaMissense

4340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:7861188:T:A	K615N	0.988
5:7861188:T:G	K615N	0.988
5:7861177:A:G	L619P	0.986
5:7861258:G:T	A592E	0.986
5:7862891:A:G	L544P	0.975
5:7861230:A:C	F601L	0.974
5:7861230:A:T	F601L	0.974
5:7861232:A:G	F601L	0.974
5:7861189:T:A	K615I	0.972
5:7859484:A:G	L647S	0.969
5:7861255:A:T	L593Q	0.961
5:7861182:T:A	R617S	0.957
5:7861182:T:G	R617S	0.957
5:7862823:C:G	D567H	0.957
5:7862860:A:C	F554L	0.957
5:7862860:A:T	F554L	0.957
5:7862862:A:G	F554L	0.957
5:7861255:A:C	L593R	0.954
5:7861163:A:C	Y624D	0.953
5:7861255:A:G	L593P	0.952
5:7862891:A:C	L544R	0.946
5:7861177:A:T	L619Q	0.944
5:7861643:A:C	I570S	0.944
5:7867464:C:G	R207P	0.943
5:7862891:A:T	L544Q	0.942
5:7861643:A:G	I570T	0.941
5:7861162:T:G	Y624S	0.937
5:7862882:A:G	L547P	0.936
5:7861189:T:G	K615T	0.933
5:7861643:A:T	I570N	0.932

dbSNP variants (sampled 300 via entrez): RS1000070228 (5:7868253 C>A,T), RS1000241404 (5:7870983 T>A,G), RS1000340924 (5:7864883 G>A,T), RS1000390070 (5:7865170 C>T), RS1000599722 (5:7861362 T>C), RS1000677622 (5:7866762 T>C), RS1000783122 (5:7859982 T>C,G), RS1000946491 (5:7868638 G>A,C), RS1001132397 (5:7866995 G>A), RS1002007394 (5:7868016 G>C), RS1002082729 (5:7865859 C>A,T), RS1002094701 (5:7870170 C>A), RS1002136732 (5:7866225 A>C), RS1002288590 (5:7859098 T>G), RS1002567430 (5:7860822 C>T)

Disease associations

OMIM: gene MIM:617530 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

6 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1801394	Efficacy	3	sevoflurane	sedation
rs1801394	Other	3	sevoflurane
rs1801394	Toxicity	4	methotrexate	Juvenile Rheumatoid Arthritis;Rheumatoid arthritis
rs2307116	Other	3	sevoflurane
rs2307116	Efficacy	3	sevoflurane
rs3733784	Efficacy	3	sevoflurane

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801394	FASTKD3, MTRR	3	4.75	6	folic acid;vitamin b-complex;plain;methotrexate;sevoflurane
rs3733784	FASTKD3, MTRR	3	2.50	1	sevoflurane
rs2307116	FASTKD3, MTRR	3	2.00	2	sevoflurane

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Acetaminophen	decreases expression	2
Cyclosporine	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	increases expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
jinfukang	decreases expression	1
MT19c compound	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Diuron	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	decreases expression	1
Niclosamide	decreases expression	1
Urethane	decreases expression	1
Vanadates	decreases expression	1
Vitamin E	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C6Y4	HAP1 FASTKD3-sKO	Cancer cell line	Male
CVCL_C6Y7	HAP1 FASTKD3&4-dKO	Cancer cell line	Male
CVCL_SN21	HAP1 FASTKD3 (-) 1	Cancer cell line	Male
CVCL_XN69	HAP1 FASTKD3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.