ZAR1

Summary

ZAR1 (zygote arrest 1, HGNC:20436) is a protein-coding gene on chromosome 4p11, encoding Zygote arrest protein 1 (Q86SH2). mRNA-binding protein that mediates formation of MARDO (mitochondria-associated ribonucleoprotein domain), a membraneless compartment that stores maternal mRNAs in oocytes.

This maternal effect gene is oocyte-specific and encodes a protein that is thought to function in the initiation of embryogenesis. A similar protein in mouse is required for female fertility.

Source: NCBI Gene 326340 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic disease (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 84 total
• MANE Select transcript: NM_175619

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20436
Approved symbol	ZAR1
Name	zygote arrest 1
Location	4p11
Locus type	gene with protein product
Status	Approved
Aliases	Z3CXXC6
Ensembl gene	ENSG00000182223
Ensembl biotype	protein_coding
OMIM	607520
Entrez	326340

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000327939

RefSeq mRNA: 1 — MANE Select: NM_175619 NM_175619

CCDS: CCDS3483

Canonical transcript exons

ENST00000327939 — 4 exons

Exon	Start	End
ENSE00001299412	48492766	48492858
ENSE00001302506	48492938	48493012
ENSE00001319202	48490252	48491254
ENSE00001323982	48494101	48494389

Expression profiles

Bgee: expression breadth broad, 39 present calls, max score 99.49.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.49	gold quality
oocyte	CL:0000023	98.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.03	gold quality
sperm	CL:0000019	81.72	gold quality
skin of hip	UBERON:0001554	52.57	silver quality
bone marrow cell	CL:0002092	52.49	gold quality
upper leg skin	UBERON:0004262	52.38	gold quality
lower lobe of lung	UBERON:0008949	49.13	silver quality
substantia nigra	UBERON:0002038	48.03	gold quality
midbrain	UBERON:0001891	47.13	gold quality
bone marrow	UBERON:0002371	46.49	silver quality
left testis	UBERON:0004533	46.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	45.96	silver quality
testis	UBERON:0000473	45.35	gold quality
right testis	UBERON:0004534	45.03	gold quality
lateral nuclear group of thalamus	UBERON:0002736	44.54	gold quality
lateral globus pallidus	UBERON:0002476	44.19	gold quality
putamen	UBERON:0001874	43.75	gold quality
vastus lateralis	UBERON:0001379	43.54	gold quality
amniotic fluid	UBERON:0000173	43.48	gold quality
quadriceps femoris	UBERON:0001377	43.45	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	42.90	silver quality
heart right ventricle	UBERON:0002080	42.58	gold quality
pharyngeal mucosa	UBERON:0000355	42.43	gold quality
adult organism	UBERON:0007023	42.41	gold quality
ascending aorta	UBERON:0001496	42.26	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	42.23	gold quality
buccal mucosa cell	CL:0002336	42.19	gold quality
pituitary gland	UBERON:0000007	42.07	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting ZAR1, 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-3119	99.92	71.34	2390
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-6890-3P	97.50	65.71	997

Literature-anchored findings (GeneRIF, showing 12)

• The carboxyl-termini of these ZAR1 proteins contain an important functional domain that is conserved through vertebrate evolution and that may be necessary for normal female reproduction in the transition from oocyte to embryonic life. (PMID:12773403)
• Zygote arrest 1 (ZAR1) could be implicated in regulation of meiosis and post meiotic differentiation of male and female germ cells through expression of shorter splicing variants. Central role of this gene in early reproductive processes. (PMID:16551357)
• we identified a frequently aberrant methylated region within the Zygote arrest 1 (ZAR1) gene in melanoma and demonstrated a distinct methylation pattern between melanoma and nevus.The involvement of ZAR1 in the carcinogenesis of melanoma remains unclear. (PMID:20654783)
• Findings indicate that non-promoter hypermethylation of ZAR1 is extremely frequent in diffuse gliomas and pituitary adenomas, but methylation-related aberrant ZAR1 expression is far less likely to be related to glioma tumorigenesis. (PMID:21206179)
• Hypermethylation of ZAR1 regions is extremely frequent in neuroblastomas and correlates with established markers of progressive disease and outcome. (PMID:23583134)
• ZAR1 and SFRP4 qMSP could be used as potential biomarker for CC diagnosis (PMID:24787227)
• A decreased methylation level at CpG sites of ZAR1 exon 1/intron 1. CpGi could serve as a biomarker for invasive bladder cancer. (PMID:25227574)
• Study shows for the first time the lung tumor-specific epigenetic inactivation of ZAR1 due to DNA methylation of its CpG island promoter. Furthermore, ZAR1 was characterized by the ability to block tumor growth through the inhibition of cell cycle progression in cancer cell lines. (PMID:28588743)
• ZAR1 has oncogenic effects in neuroblastoma by suppressing cell differentiation via regulation of MYCN expression.Elevated ZAR1 expression level is closely related to poor prognosis of patients with neuroblastoma. (PMID:28791558)
• Study presents evidence that ZAR1, which harbors tumor suppressive properties, is a prognostic and diagnostic cancer biomarker for lung and kidney. ZAR1 suppresses tumor cell line growth in part through p53 and strongly depending on its functional zinc-finger. (PMID:31801617)
• Variation Screening of Zygote Arrest 1(ZAR1) in Women with Recurrent Zygote Arrest During IVF/ICSI Programs. (PMID:32700283)
• The ZAR1 protein in cancer; from epigenetic silencing to functional characterisation and epigenetic therapy of tumour suppressors. (PMID:32828887)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zar1	ENSDARG00000019706
mus_musculus	Zar1	ENSMUSG00000063935
rattus_norvegicus	Zar1	ENSRNOG00000026150

Paralogs (1): ZAR1L (ENSG00000189167)

Protein

Protein identifiers

Zygote arrest protein 1 — Q86SH2 (reviewed: Q86SH2)

All UniProt accessions (1): Q86SH2

UniProt curated annotations — full annotation on UniProt →

Function. mRNA-binding protein that mediates formation of MARDO (mitochondria-associated ribonucleoprotein domain), a membraneless compartment that stores maternal mRNAs in oocytes. MARDO assembly around mitochondria is directed by an increase in mitochondrial membrane potential during oocyte growth. Promotes formation of MARDO phase-separated membraneless compartment by undergoing liquid-liquid phase separation upon binding to maternal mRNAs. Binds to the 3’-UTR of maternal mRNAs. Maternal mRNAs stored in the MARDO are translationally repressed. Essential for female fertility and oocyte-to-embryo transition by coordinating maternal mRNA storage, translation and degradation.

Subunit / interactions. Interacts with YBX2.

Subcellular location. Cytoplasm. Cytoplasmic ribonucleoprotein granule.

Tissue specificity. Ovary and testis.

Post-translational modifications. Ubiquitinated and degradaded by the proteasome during oocyte meiotic maturation, leading to MARDO (mitochondria-associated ribonucleoprotein domain) membraneless compartment dissolution.

Domain organisation. Disordered region at the N-terminus undergoes liquid-liquid phase separation (LLPS) for the formation of MARDO (mitochondria-associated ribonucleoprotein domain), a membraneless compartment that stores maternal mRNAs in oocytes. The 3CxxC-type mediates binding to the 3’-UTR of mRNAs.

Similarity. Belongs to the ZAR1 family.

RefSeq proteins (1): NP_783318* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026775	Zar1	Family
IPR027377	ZAR1/RTP1-5-like_Znf-3CxxC	Domain

Pfam: PF13695

UniProt features (6 total): region of interest 2, compositionally biased region 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9JKO	X-RAY DIFFRACTION	1.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86SH2-F1	55.78	0.11

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_CELL_MATURATION, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_OOCYTE_MATURATION, GOBP_OOCYTE_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, chr4p11

GO Biological Process (7): oocyte maturation (GO:0001556), translation (GO:0006412), negative regulation of translation (GO:0017148), mRNA stabilization (GO:0048255), membraneless organelle assembly (GO:0140694), cell differentiation (GO:0030154), oogenesis (GO:0048477)

GO Molecular Function (8): mRNA 3’-UTR binding (GO:0003730), zinc ion binding (GO:0008270), RNA sequestering activity (GO:0140610), molecular condensate scaffold activity (GO:0140693), RNA binding (GO:0003723), mRNA binding (GO:0003729), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), ribonucleoprotein granule (GO:0035770), cytoplasmic ribonucleoprotein granule (GO:0036464), intracellular membraneless organelle (GO:0043232)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA binding	2
intracellular anatomical structure	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
regulation of mRNA stability	1
RNA stabilization	1
negative regulation of mRNA catabolic process	1
organelle assembly	1
cellular developmental process	1
germ cell development	1
female gamete generation	1
mRNA binding	1
transition metal ion binding	1
molecular sequestering activity	1
protein-macromolecule adaptor activity	1
nucleic acid binding	1
binding	1
cation binding	1
cellular anatomical structure	1
intracellular membraneless organelle	1
supramolecular complex	1
cytoplasm	1
ribonucleoprotein granule	1
membraneless organelle	1
intracellular organelle	1

Protein interactions and networks

STRING

530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZAR1	GDF9	O60383	965
ZAR1	NLRP5	P59047	719
ZAR1	BMP15	O95972	676
ZAR1	H1-8	Q8IZA3	647
ZAR1	NPM2	Q86SE8	641
ZAR1	OOEP	A6NGQ2	609
ZAR1	PADI6	Q6TGC4	591
ZAR1	FIGLA	Q6QHK4	553
ZAR1	ZP2	Q05996	551
ZAR1	ZP3	P21754	544
ZAR1	ZP1	P60852	536
ZAR1	CCNB1	P14635	526
ZAR1	NOBOX	O60393	519
ZAR1	KHDC3L	Q587J8	512
ZAR1	TLE6	Q9H808	507

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ZAR1	DYNLL2	psi-mi:“MI:0915”(physical association)	0.560
ZAR1	DYNLL2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): DYNLL2 (Two-hybrid), CRABP2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0U1RR11, A0A0U1RRI6, A6NCS6, A6NJG2, B0BN44, D3YXK1, E9PY61, E9Q0B3, F5H4A9, O00220, O00221, P09038, P0DPI3, P22083, P98077, Q08AU9, Q2M2W7, Q2M3V2, Q2TBI2, Q5F267, Q5FW56, Q5IS69, Q5R866, Q5T4W7, Q5TM52, Q5U4P2, Q5VTJ3, Q659K9, Q673H1, Q69ZB3, Q6AYE8, Q6IPT2, Q6PJ61, Q7RTU4, Q7TSX9, Q7YR31, Q80SU3, Q86SH2, Q86Y97, Q8NBR0

Diamond homologs: A0A1L8HBI7, A0A1L8HJK9, A0A1L8HTT5, A6NP61, C0SPG1, C3VD30, K7SGN7, Q1XFL1, Q7T3T8, Q7T3T9, Q7T3U0, Q7TSX9, Q80SU3, Q86SH2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	81
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

509 predictions. Top by Δscore:

Variant	Effect	Δscore
4:48493009:TC:T	donor_gain	1.0000
4:48493013:G:GG	donor_gain	1.0000
4:48492764:A:AG	acceptor_gain	0.9900
4:48492765:G:GG	acceptor_gain	0.9900
4:48493059:GGTTT:G	donor_gain	0.9900
4:48491250:TCCAG:T	donor_loss	0.9800
4:48491251:CCAGG:C	donor_loss	0.9800
4:48491252:CAGGT:C	donor_loss	0.9800
4:48491253:AGGTA:A	donor_loss	0.9800
4:48491254:GGTA:G	donor_loss	0.9800
4:48491255:G:A	donor_loss	0.9800
4:48491256:T:G	donor_loss	0.9800
4:48492854:ACAAG:A	donor_loss	0.9800
4:48492855:CAAGG:C	donor_loss	0.9800
4:48492857:AGG:A	donor_loss	0.9800
4:48492858:GGTAA:G	donor_loss	0.9800
4:48492859:GTAA:G	donor_loss	0.9800
4:48492860:T:A	donor_loss	0.9800
4:48494100:GAGTT:G	acceptor_gain	0.9800
4:48492861:AA:A	donor_loss	0.9700
4:48494100:GA:G	acceptor_gain	0.9700
4:48493069:AT:A	donor_gain	0.9500
4:48493008:GTCAA:G	donor_gain	0.9400
4:48493060:GTTT:G	donor_gain	0.9300
4:48493061:TTTT:T	donor_gain	0.9300
4:48493062:TTTT:T	donor_gain	0.9300
4:48493072:GTT:G	donor_gain	0.9300
4:48493073:TTT:T	donor_gain	0.9300
4:48494099:A:AG	acceptor_gain	0.9300
4:48494100:G:GG	acceptor_gain	0.9300

AlphaMissense

2693 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:48492819:G:C	W339C	1.000
4:48492819:G:T	W339C	1.000
4:48492817:T:A	W339R	0.999
4:48492817:T:C	W339R	0.999
4:48492835:T:A	W345R	0.999
4:48492835:T:C	W345R	0.999
4:48492837:G:C	W345C	0.999
4:48492837:G:T	W345C	0.999
4:48492956:T:C	C359R	0.999
4:48494179:T:C	C404R	0.999
4:48494188:T:A	C407S	0.999
4:48494188:T:C	C407R	0.999
4:48494189:G:C	C407S	0.999
4:48492796:T:A	C332S	0.998
4:48492796:T:C	C332R	0.998
4:48492797:G:A	C332Y	0.998
4:48492797:G:C	C332S	0.998
4:48492798:C:G	C332W	0.998
4:48492823:A:C	S341R	0.998
4:48492825:T:A	S341R	0.998
4:48492825:T:G	S341R	0.998
4:48492838:T:C	C346R	0.998
4:48492840:T:G	C346W	0.998
4:48492944:T:C	F355L	0.998
4:48492946:C:A	F355L	0.998
4:48492946:C:G	F355L	0.998
4:48492956:T:A	C359S	0.998
4:48492957:G:A	C359Y	0.998
4:48492957:G:C	C359S	0.998
4:48492958:C:G	C359W	0.998

dbSNP variants (sampled 300 via entrez): RS10008444 (4:48490417 G>A,C,T), RS1000930871 (4:48497262 A>G), RS1000984887 (4:48496978 AATG>A), RS1001129638 (4:48491385 C>G,T), RS1001298472 (4:48491116 G>A), RS1001518874 (4:48491630 T>C,G), RS1001582578 (4:48490953 A>G), RS10018344 (4:48496653 C>A,G,T), RS1002452427 (4:48496660 CTA>C), RS10029732 (4:48496662 A>C,G), RS10031120 (4:48490196 C>G,T), RS10031777 (4:48496273 T>C,G), RS1003452443 (4:48495284 T>C,G), RS1003524575 (4:48489985 G>GT), RS1004784366 (4:48497755 T>C)

Disease associations

OMIM: gene MIM:607520 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Limited	Autosomal recessive

Mondo (1): syndromic disease (MONDO:0002254)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005863_11	Menopause (age at onset)	3.000000e-15
GCST005863_23	Menopause (age at onset)	4.000000e-15
GCST008103_79	Bipolar disorder	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013577	Syndrome	C23.550.288.500

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
titanium dioxide	increases methylation	1
theaflavin-3,3’-digallate	affects expression	1
Benzo(a)pyrene	affects methylation	1
Methotrexate	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00027456	PHASE2	COMPLETED	Leptin to Treat Severe Insulin Resistance - Pilot Study
NCT00213447	Not specified	COMPLETED	T Cell Response in Hypersensitivity Syndrome
NCT02240888	Not specified	COMPLETED	Vaccination in Inflammatory Rheumatic Disease (VACCIMIL). The Impact of Antirheumatic Treatment on Antibody Response
NCT02526082	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of the Helsinki Businessmen Study
NCT02637518	Not specified	UNKNOWN	Comprehensive Validation of Frailty Assessment Tools in Older Adults in Different Clinical and Social Settings
NCT02971072	Not specified	COMPLETED	Neurophysiology of Weakness and Exercise in Rotator Cuff Tendinopathy
NCT02974569	Not specified	COMPLETED	Improving Symptom Self-management in Adolescents & Young Adults With Cancer
NCT03265561	Not specified	COMPLETED	Spinal Infection Management With Structural Allograft
NCT04190342	Not specified	COMPLETED	Effects of a Traditional Chinese Exercise Program on Symptom Cluster in Breast Cancer Patients
NCT04874584	Not specified	COMPLETED	Culturally Tailored Nurse Coaching Study for Cancer Symptom Management
NCT04909489	Not specified	UNKNOWN	PDR and SKYD of Dyslipidemia’s Characteristics From the Oxidative Stress Enhancement Caused by Inhibition of Serine Metabolic Pathway
NCT05218122	Not specified	UNKNOWN	Characteristics of LKDS and PBSS of KOA Based on the Enhancement of Inflammatory Response by TGF-β/Smad Pathway Inhibited
NCT05266118	Not specified	COMPLETED	Patient Reported Symptoms the First Week After Intensive Care Unit Discharge and up to Hospital Discharge
NCT05321966	Not specified	COMPLETED	The Effect of Video Training on Symptom Burden Patients Undergoing Hemodialysis Treatment
NCT05818748	Not specified	UNKNOWN	Effect Of Virtual Reality Distraction on Symptom Control and Anxiety in Children With Leukemia
NCT05837988	Not specified	UNKNOWN	Construction of Symptom Network in Maintenance Hemodialysis Patients
NCT06143436	Not specified	UNKNOWN	TCM Constitution, Pattern Types, and Disease Factors in Primary Lung Cancer.
NCT06222008	Not specified	UNKNOWN	Study on Symptom Clusters During Chemotherapy in Ovarian Cancer Patients With Different Chinese Medicine Constitution
NCT06412107	Not specified	COMPLETED	Somatic Acupressure for Symptom Cluster Management in Breast Cancer Survivors
NCT06847360	Not specified	RECRUITING	Home-based Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) for IBS Pain
NCT07281300	Not specified	RECRUITING	Mindfulness-Oriented Respiratory Distress Symptom Intervention for Lung Cancer
NCT07315672	Not specified	RECRUITING	Acupressure for Cough in Lung Cancer Survivors
NCT07479654	Not specified	NOT_YET_RECRUITING	AI-Enabled Frailty Risk Prediction in Adult Congenital Heart Disease
NCT07495358	Not specified	NOT_YET_RECRUITING	Development and Usability Evaluation of a Knowledge Graph-Based Symptom Management System for Patients With Breast Cancer Undergoing Chemotherapy
NCT07576114	Not specified	RECRUITING	Comparison of Gluteal Muscle Activation and Core Strengthening in Dead Butt Syndrome Syndrome