RTL1

Summary

RTL1 (retrotransposon Gag like 1, HGNC:14665) is a protein-coding gene on chromosome 14q32.2, encoding Retrotransposon-like protein 1 (A6NKG5). Plays an essential role in capillaries endothelial cells for the maintenance of feto-maternal interface and for development of the placenta.

This gene is a retrotransposon-derived, paternally expressed imprinted gene that is highly expressed at the late fetal stage in both the fetus and placenta. It has an overlapping maternally expressed antisense transcript, which contains several microRNAs targeting the transcripts of this gene through an RNA interference (RNAi) mechanism. This gene is essential for maintenance of the fetal capillaries.

Source: NCBI Gene 388015 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 219 total
• Phenotypes (HPO): 169
• MANE Select transcript: NM_001134888

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14665
Approved symbol	RTL1
Name	retrotransposon Gag like 1
Location	14q32.2
Locus type	gene with protein product
Status	Approved
Aliases	PEG11, MART1, Mar1, SIRH2, HUR1
Ensembl gene	ENSG00000254656
Ensembl biotype	protein_coding
OMIM	611896
Entrez	388015

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000649591

RefSeq mRNA: 2 — MANE Select: NM_001134888 NM_001134888, NM_001425285

CCDS: CCDS53910

Canonical transcript exons

ENST00000649591 — 4 exons

Exon	Start	End
ENSE00003832034	100879753	100884874
ENSE00003836409	100903605	100903722
ENSE00003839549	100903291	100903386
ENSE00003840561	100893444	100893505

Expression profiles

Bgee: expression breadth broad, 44 present calls, max score 81.61.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1118 / max 81.8391, expressed in 26 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144955	0.1118	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	81.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.39	silver quality
placenta	UBERON:0001987	72.13	gold quality
hypothalamus	UBERON:0001898	66.05	gold quality
sural nerve	UBERON:0015488	64.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	58.66	silver quality
colonic epithelium	UBERON:0000397	58.02	gold quality
adrenal gland	UBERON:0002369	54.07	gold quality
substantia nigra	UBERON:0002038	53.59	gold quality
left adrenal gland cortex	UBERON:0035825	52.16	gold quality
left ovary	UBERON:0002119	51.62	gold quality
right adrenal gland	UBERON:0001233	51.56	gold quality
ovary	UBERON:0000992	51.19	gold quality
stromal cell of endometrium	CL:0002255	50.38	silver quality
right ovary	UBERON:0002118	50.18	gold quality
left adrenal gland	UBERON:0001234	49.75	gold quality
right adrenal gland cortex	UBERON:0035827	49.28	gold quality
skeletal muscle tissue	UBERON:0001134	48.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	47.71	gold quality
muscle tissue	UBERON:0002385	46.41	gold quality
nucleus accumbens	UBERON:0001882	46.14	gold quality
gall bladder	UBERON:0002110	44.51	silver quality
temporal lobe	UBERON:0001871	43.81	gold quality
amygdala	UBERON:0001876	43.66	gold quality
primary visual cortex	UBERON:0002436	43.16	gold quality
tonsil	UBERON:0002372	42.62	silver quality
brain	UBERON:0000955	42.35	gold quality
islet of Langerhans	UBERON:0000006	42.28	silver quality
adenohypophysis	UBERON:0002196	41.63	gold quality
anterior cingulate cortex	UBERON:0009835	41.41	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NEUROG2

Literature-anchored findings (GeneRIF, showing 7)

• RTL1, a paternally expressed gene in a cluster of imprinted genes on chromosome 14q32.2, is associated with upd(14)pat-like and upd(14)mat-like phenotypes. (PMID:18176563)
• In addition to identifying Rtl1 as a novel driver of HCC, our study represents one of the first direct in vivo demonstrations of a role for such a co-opted genetic element in promoting carcinogenesis. (PMID:23593033)
• The results of this study suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia. (PMID:24389010)
• Data suggest that DNA is differentially methylated (hypomethylated) at a gene locus associated with regulation of expression of RTL1 and miR136 in type 1 diabetes; these studies were conducted using tissue bank placentas and whole blood cell DNA from children with type 1 diabetes. (RTL1 = retrotransposon-like protein 1; miR136 = microRNA 136) (PMID:27174469)
• We find that placental expression of DIO3 and RTL1) correlates with prenatal growth. Combined, these findings suggest that epigenetic programming and gene expression within the DLK1-DIO3 imprinted domain influence both prenatal and postnatal growth. (PMID:28502757)
• The role of eutherian-specific RTL1 in the nervous system and its implications for the Kagami-Ogata and Temple syndromes. (PMID:33484574)
• Expression profiling of RTL1 in human breast cancer tissues and cell lines. (PMID:34087231)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000109342
mus_musculus	Peg10	ENSMUSG00000092035

Paralogs (10): RTL8C (ENSG00000134590), RTL3 (ENSG00000179300), LDOC1 (ENSG00000182195), RTL4 (ENSG00000187823), RTL6 (ENSG00000188636), RTL8A (ENSG00000203950), RTL8B (ENSG00000212747), RTL10 (ENSG00000215012), PEG10 (ENSG00000242265), RTL5 (ENSG00000242732)

Protein

Protein identifiers

Retrotransposon-like protein 1 — A6NKG5 (reviewed: A6NKG5)

Alternative names: Mammalian retrotransposon derived protein 1, Paternally expressed gene 11 protein, Retrotransposon-derived protein PEG11

All UniProt accessions (1): A6NKG5

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in capillaries endothelial cells for the maintenance of feto-maternal interface and for development of the placenta.

Subcellular location. Membrane.

Miscellaneous. Rtl1 is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes. RTL1 is an imprinted gene located in a cluster of imprinted genes on chromosome 14. It is expressed from the paternal chromosome and has an antisense transcript with full complementarity to RTL1, RTL1as, expressed from the maternal chromosome, which acts as a repressor for RTL1. Excessive RTL1 expression and decreased RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively. Paternal and maternal uniparental disomy for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes; Upd(14)pat results in a unique phenotype characterized by facial abnormality, a small, bell-shaped thorax and abdominal wall defects, and upd(14)mat leads to pre- and postnatal growth failure and early onset of puberty.

RefSeq proteins (2): NP_001128360, NP_001412214 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021109	Peptidase_aspartic_dom_sf	Homologous_superfamily
IPR032549	RTL1/1-8/LDOC_capsid-like	Domain
IPR032567	RTL1-rel	Family
IPR041577	RT_RNaseH_2	Domain
IPR043128	Rev_trsase/Diguanyl_cyclase	Homologous_superfamily
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily

Pfam: PF16297, PF17919

UniProt features (15 total): compositionally biased region 7, region of interest 4, transmembrane region 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NKG5-F1	58.74	0.11

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 399 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, GOBP_PLACENTA_DEVELOPMENT, chr14q32, HP_INGUINAL_HERNIA, HP_CRYPTORCHIDISM, HP_TALL_STATURE, HP_ABNORMALITY_OF_THE_TONGUE, HP_MACROGLOSSIA, HP_ABNORMAL_LIP_MORPHOLOGY, HP_NARROW_MOUTH, HP_ABNORMAL_UVULA_MORPHOLOGY, HP_ABNORMAL_PALATE_MORPHOLOGY, HP_ABNORMAL_UPPER_LIP_MORPHOLOGY

GO Biological Process (0):

GO Molecular Function (0):

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	1

Protein interactions and networks

STRING

784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTL1	DLK1	P15803	917
RTL1	DIO3	P55073	791
RTL1	RTL4	Q6ZR62	628
RTL1	TP53	P04637	613
RTL1	RTL6	Q6ICC9	597
RTL1	BEGAIN	Q9BUH8	596
RTL1	GRB10	Q13322	507
RTL1	NAP1L5	Q96NT1	498
RTL1	PEG3	P78418	479
RTL1	TMC6	Q7Z403	448
RTL1	MEST	Q5EB52	441
RTL1	WDR20	Q8TBZ3	439
RTL1	IGF2	P01344	437
RTL1	SGCE	O43556	436
RTL1	PLAGL1	Q9UM63	434

IntAct

3 interactions, top by confidence:

A	B	Type	Score
APP	RTL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): RTL1 (Affinity Capture-MS), RTL1 (Affinity Capture-MS), RTL1 (Affinity Capture-MS), RTL1 (Affinity Capture-MS), RTL1 (Affinity Capture-MS), RTL1 (Affinity Capture-MS), RTL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B7P3V8, A4FUB7, A4H7G5, A4HVU6, A6NKG5, B4NSS9, B6EU02, F4I1N8, H2KZW3, O10318, O13329, P04586, P0C2J7, P18475, P34601, P47024, Q01577, Q05101, Q09178, Q09293, Q1L6Q1, Q3S4A7, Q4DCH3, Q4QFY1, Q4R6I1, Q52QI2, Q57X81, Q5RBK0, Q5RDX4, Q62120, Q66H30, Q6R2W3, Q7KLI1, Q7LHG5, Q8CDM1, Q8K259, Q8N157, Q90179, Q91829, Q99315

Diamond homologs: A6NKG5, A6ZKI3, O95751, Q17QF6, Q17RB0, Q1JQ94, Q52QI2, Q5DTZ0, Q5HYW3, Q6SEH4, Q6SEH5, Q7M732, Q7TPY9, Q9BWD3, Q505G4, Q6ICC9, Q7TN75, Q86TG7, Q8N8U3, A1Z651, O92815, P03355, P03356, P03358, P03359, P03360, P04026, P04584, P04589, P05895, P08361, P10272, P10273, P10400, P11227, P16103, P16901, P17757, P18042, P18096

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	181
Likely benign	28
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

397 predictions. Top by Δscore:

Variant	Effect	Δscore
14:100892973:GGTT:G	donor_gain	0.7900
14:100892970:C:T	donor_gain	0.7100
14:100893799:GAAGA:G	acceptor_gain	0.7000
14:100893281:GCCT:G	donor_gain	0.6800
14:100893139:G:GT	donor_gain	0.6700
14:100892975:TTTA:T	donor_gain	0.6600
14:100893580:A:AG	acceptor_gain	0.6400
14:100893581:G:GG	acceptor_gain	0.6400
14:100893758:A:G	acceptor_gain	0.6400
14:100893799:GAA:G	acceptor_gain	0.6400
14:100892969:G:GT	donor_gain	0.6300
14:100893321:GAC:G	acceptor_gain	0.6300
14:100893141:GGTC:G	donor_gain	0.6200
14:100893798:A:AG	acceptor_gain	0.6200
14:100893799:G:GG	acceptor_gain	0.6200
14:100893134:GA:G	donor_gain	0.6000
14:100893791:A:AG	acceptor_gain	0.6000
14:100893142:GTC:G	donor_gain	0.5900
14:100893143:TCT:T	donor_gain	0.5900
14:100893144:CTC:C	donor_gain	0.5900
14:100893748:A:AG	acceptor_gain	0.5900
14:100893140:GGGTC:G	donor_gain	0.5800
14:100893320:A:AG	acceptor_gain	0.5800
14:100893321:G:GG	acceptor_gain	0.5800
14:100893728:TTACA:T	acceptor_loss	0.5700
14:100893729:TACAG:T	acceptor_loss	0.5700
14:100893730:ACAGG:A	acceptor_loss	0.5700
14:100893731:CAGG:C	acceptor_loss	0.5700
14:100893732:AGGTT:A	acceptor_loss	0.5700
14:100893733:GGTT:G	acceptor_loss	0.5700

AlphaMissense

8929 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:100883267:A:G	W508R	0.997
14:100883267:A:T	W508R	0.997
14:100881989:A:G	W934R	0.995
14:100881989:A:T	W934R	0.995
14:100883092:A:G	F566S	0.995
14:100884141:G:C	F216L	0.995
14:100884141:G:T	F216L	0.995
14:100884143:A:G	F216L	0.995
14:100883104:A:G	L562P	0.994
14:100883461:G:T	A443D	0.994
14:100881858:G:C	F977L	0.993
14:100881858:G:T	F977L	0.993
14:100881860:A:G	F977L	0.993
14:100883091:A:C	F566L	0.993
14:100883091:A:T	F566L	0.993
14:100883093:A:G	F566L	0.993
14:100883199:G:C	C530W	0.993
14:100883840:A:G	W317R	0.993
14:100883840:A:T	W317R	0.993
14:100882066:C:G	R908P	0.992
14:100882531:A:G	L753P	0.992
14:100882792:A:G	L666P	0.992
14:100883201:A:G	C530R	0.992
14:100883800:A:G	L330P	0.992
14:100882485:G:C	S768R	0.991
14:100882485:G:T	S768R	0.991
14:100882487:T:G	S768R	0.991
14:100882630:A:G	L720P	0.991
14:100883049:G:C	S580R	0.991
14:100883049:G:T	S580R	0.991

dbSNP variants (sampled 300 via entrez): RS1000122182 (14:100898196 A>G,T), RS1000212566 (14:100885599 C>T), RS1000267233 (14:100880894 T>A), RS1000294360 (14:100896900 A>AT), RS1000317571 (14:100881905 G>A), RS1000568738 (14:100901868 C>G), RS1000583179 (14:100902051 C>A,T), RS1000684754 (14:100900466 T>C), RS1000912587 (14:100895758 G>T), RS1000984978 (14:100892159 C>A,G), RS1001116800 (14:100896917 C>G,T), RS1001528489 (14:100897047 T>C), RS1001641390 (14:100892427 C>T), RS1001789254 (14:100899279 G>A), RS1001961204 (14:100901214 C>T)

Disease associations

OMIM: gene MIM:611896 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

169 total (30 of 169 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000158	Macroglossia
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000260	Wide anterior fontanel
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000403	Recurrent otitis media
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000490	Deeply set eye
HP:0000565	Esotropia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000539_2	Type 1 diabetes	1.000000e-10
GCST003225_29	Pelvic organ prolapse (moderate/severe)	3.000000e-07
GCST008477_1	Emphysema annual change measurement in smokers (adjusted lung density)	6.000000e-06
GCST008477_19	Emphysema annual change measurement in smokers (adjusted lung density)	8.000000e-06
GCST90013405_56	Liver enzyme levels (alanine transaminase)	6.000000e-57
GCST90016669_2	Pancreas volume	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
alpha phellandrene	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
abrine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Chlordan	increases expression	1
Phenobarbital	increases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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