MAB21L2

Summary

MAB21L2 (mab-21 like 2, HGNC:6758) is a protein-coding gene on chromosome 4q31.3, encoding Protein mab-21-like 2 (Q9Y586). Required for several aspects of embryonic development including normal development of the eye.

This gene is similar to the C. elegans MAB-21 cell fate-determining gene, a downstream target of transforming growth factor-beta signaling. It is thought that this gene may be involved in neural development. The protein encoded by this gene is primarily nuclear, although some cytoplasmic localization has been observed.

Source: NCBI Gene 10586 — RefSeq curated summary.

At a glance

• Gene–disease (curated): colobomatous microphthalmia-rhizomelic dysplasia syndrome (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 7 total — 3 pathogenic
• Phenotypes (HPO): 27
• MANE Select transcript: NM_006439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6758
Approved symbol	MAB21L2
Name	mab-21 like 2
Location	4q31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000181541
Ensembl biotype	protein_coding
OMIM	604357
Entrez	10586

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000317605

RefSeq mRNA: 1 — MANE Select: NM_006439 NM_006439

CCDS: CCDS3774

Canonical transcript exons

ENST00000317605 — 1 exons

Exon	Start	End
ENSE00001257263	150582151	150584693

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 96.93.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3671 / max 386.1424, expressed in 308 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49989	0.6726	225
49991	0.4559	187
49987	0.3745	181
49988	0.3465	176
49993	0.2787	160
49992	0.1283	69
49990	0.0712	31
49994	0.0396	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	96.93	gold quality
pons	UBERON:0000988	94.17	gold quality
pigmented layer of retina	UBERON:0001782	94.07	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.94	gold quality
colon	UBERON:0001155	87.33	gold quality
synovial joint	UBERON:0002217	87.14	gold quality
large intestine	UBERON:0000059	87.05	gold quality
intestine	UBERON:0000160	86.06	gold quality
superior vestibular nucleus	UBERON:0007227	86.01	gold quality
transverse colon	UBERON:0001157	85.69	gold quality
calcaneal tendon	UBERON:0003701	85.03	gold quality
cranial nerve II	UBERON:0000941	84.23	gold quality
caecum	UBERON:0001153	84.23	gold quality
cartilage tissue	UBERON:0002418	84.10	gold quality
colonic epithelium	UBERON:0000397	83.54	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.17	gold quality
medulla oblongata	UBERON:0001896	83.02	gold quality
small intestine	UBERON:0002108	82.89	gold quality
tibia	UBERON:0000979	81.76	gold quality
vermiform appendix	UBERON:0001154	81.21	gold quality
layer of synovial tissue	UBERON:0007616	80.92	gold quality
inferior olivary complex	UBERON:0002127	80.09	gold quality
rectum	UBERON:0001052	78.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.16	silver quality
choroid plexus epithelium	UBERON:0003911	77.15	gold quality
secondary oocyte	CL:0000655	77.12	gold quality
duodenum	UBERON:0002114	75.50	gold quality
ileal mucosa	UBERON:0000331	74.95	gold quality
minor salivary gland	UBERON:0001830	73.75	gold quality
tendon	UBERON:0000043	73.69	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	5.19
E-ANND-3	no	0.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX6

miRNA regulators (miRDB)

108 targeting MAB21L2, 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-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
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-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Literature-anchored findings (GeneRIF, showing 5)

• This report provides compelling human genomic and genetic evidence that mutations in MAB21L2 cause major eye malformations. (PMID:24906020)
• These findings support the identification of MAB21L2 as a novel factor involved in human coloboma and highlight the power of genome editing manipulation in model organisms for analysis of the effects of whole exome variation in humans. (PMID:25719200)
• The two unrelated individuals with a novel oculo-skeletal syndrome with intellectual disability described are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2. (PMID:26116559)
• mab21 gene family members, mab21l1 and mab21l2, play important roles in regulating eye development. [review] (PMID:27558071)
• Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development. (PMID:39455595)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mab21l2	ENSMUSG00000057777
rattus_norvegicus	Mab21l2	ENSRNOG00000031398
drosophila_melanogaster	CG4766	FBGN0027546
drosophila_melanogaster	mab-21	FBGN0029003
caenorhabditis_elegans		WBGENE00003112

Paralogs (9): ITPRIP (ENSG00000148841), CGAS (ENSG00000164430), MAB21L4 (ENSG00000172478), MAB21L3 (ENSG00000173212), MB21D2 (ENSG00000180611), MAB21L1 (ENSG00000180660), TMEM102 (ENSG00000181284), ITPRIPL1 (ENSG00000198885), ITPRIPL2 (ENSG00000205730)

Protein

Protein identifiers

Protein mab-21-like 2 — Q9Y586 (reviewed: Q9Y586)

All UniProt accessions (1): Q9Y586

UniProt curated annotations — full annotation on UniProt →

Function. Required for several aspects of embryonic development including normal development of the eye.

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Microphthalmia/coloboma and skeletal dysplasia syndrome (MCSKS) [MIM:615877] A disease characterized by bilateral colobomatous microphthalmia or bilateral anophthalmia, associated with skeletal dysplasia in some cases. Additional ocular findings include microcornea, cataracts, corectopia and nystagmus. Intellectual disability is present in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the mab-21 family.

RefSeq proteins (1): NP_006430* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024810	MAB21L/cGLR	Family
IPR046903	Mab-21-like_nuc_Trfase	Domain
IPR046906	Mab-21_HhH/H2TH-like	Domain

Pfam: PF03281, PF20266

UniProt features (7 total): sequence variant 5, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y586-F1	95.11	0.91

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 210 (showing top): AAGCAAT_MIR137, GOBP_BODY_MORPHOGENESIS, BENPORATH_ES_WITH_H3K27ME3, NKX25_02, GGGTGGRR_PAX4_03, SHEPARD_BMYB_MORPHOLINO_DN, WOO_LIVER_CANCER_RECURRENCE_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, IRF1_Q6, RIGGI_EWING_SARCOMA_PROGENITOR_DN, TGIF_01, HFH4_01, LYF1_01, NKX25_01, HNF1_C

GO Biological Process (6): eye development (GO:0001654), nervous system development (GO:0007399), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), embryonic body morphogenesis (GO:0010172), camera-type eye development (GO:0043010)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory organ development	1
visual system development	1
system development	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
body morphogenesis	1
embryonic morphogenesis	1
eye development	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAB21L2	TGFB1	P01137	554
MAB21L2	PAX6	P26367	502
MAB21L2	IMPG2	Q9BZV3	447
MAB21L2	OLFM3	Q96PB7	446
MAB21L2	FOXE3	Q13461	433
MAB21L2	OTX2	P32243	408
MAB21L2	SIX3	O95343	396
MAB21L2	RBM24	Q9BX46	393
MAB21L2	VAX1	Q5SQQ9	392
MAB21L2	BMP4	P12644	386
MAB21L2	MAP3K9	P80192	385
MAB21L2	EYA1	Q99502	383
MAB21L2	KHDRBS2	Q5VWX1	381
MAB21L2	LHX2	P50458	381
MAB21L2	UNC5D	Q6UXZ4	374

IntAct

48 interactions, top by confidence:

A	B	Type	Score
MEIS2	PBX1	psi-mi:“MI:0914”(association)	0.660
CCDC102B	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
KRT40	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
MAB21L2	PNMA1	psi-mi:“MI:0915”(physical association)	0.560
MAB21L2	CCDC102B	psi-mi:“MI:0915”(physical association)	0.560
MAB21L2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
KRT31	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
CEP70	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
ARID5A	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
GOLGA6L9	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
AP1S2	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
KRT34	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
ABI1	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
TFIP11	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
MAB21L2	MEIS1	psi-mi:“MI:0914”(association)	0.530
MAB21L2	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAB21L2	PTBP1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAB21L2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
MAB21L2	MEOX2	psi-mi:“MI:0915”(physical association)	0.000
MAB21L2	KRT31	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (159): MAB21L2 (Two-hybrid), MAB21L2 (Two-hybrid), CCDC102B (Two-hybrid), KRT40 (Two-hybrid), INA (Affinity Capture-MS), MEIS1 (Affinity Capture-MS), MEIS2 (Affinity Capture-MS), PBX1 (Affinity Capture-MS), PBX2 (Affinity Capture-MS), PBX3 (Affinity Capture-MS), MIEF1 (Affinity Capture-MS), EDRF1 (Affinity Capture-MS), PNMA1 (Two-hybrid), MEIS2 (Affinity Capture-MS), MEIS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2B4RP11, A0A3M6TIF0, A0A482WD11, A0A6J1SUS3, A0A8B6XWW9, A0A913XCT1, A1ZA55, A4FV14, A4IIW0, A7SFB5, A8DYP7, A8E4S7, B3NQ14, B4QGZ2, D6WI29, D7Y2H2, O70299, P0DV11, P0DV12, P0DX69, P0DX77, P0DXB4, P0DXB5, P0DXB6, P0DXB7, P0DXB8, P0DXC0, Q0IES7, Q0IES8, Q0V9X7, Q13394, Q20054, Q29H55, Q29H56, Q5BKD0, Q5MYT9, Q5TW90, Q60856, Q6DCQ5, Q6GQD9

Diamond homologs: A4FV14, A4IIW0, O70299, Q0IES7, Q0IES8, Q0V9X7, Q13394, Q20054, Q29H55, Q29H56, Q5TW90, Q6DCQ5, Q6GQD9, Q6NYB4, Q7QHX4, Q8AY65, Q8BPP1, Q8UUZ1, Q9GQ38, Q9I9K2, Q9U3W6, Q9Y106, Q9Y586, A0A3M6TIF0, A2ASA8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1299534	NM_006439.5(MAB21L2):c.881C>A (p.Ser294Ter)	Pathogenic
427785	NM_006439.5(MAB21L2):c.151C>G (p.Arg51Gly)	Pathogenic
915998	GRCh37/hg19 4q31.3(chr4:151441408-151719830)	Pathogenic

SpliceAI

72 predictions. Top by Δscore:

Variant	Effect	Δscore
4:150583074:C:CT	donor_gain	0.8000
4:150583075:T:TT	donor_gain	0.8000
4:150584687:A:C	donor_gain	0.7900
4:150584681:CT:C	donor_gain	0.7800
4:150584682:TT:T	donor_gain	0.7800
4:150584683:TT:T	donor_gain	0.7800
4:150582917:A:C	donor_gain	0.6400
4:150583075:TA:T	donor_gain	0.6000
4:150583262:TC:T	donor_gain	0.5900
4:150582537:G:GT	donor_gain	0.5400
4:150584228:ATCCG:A	acceptor_gain	0.5200
4:150583074:CTACA:C	donor_gain	0.5000
4:150583263:C:CT	donor_gain	0.5000
4:150583264:T:TT	donor_gain	0.5000
4:150582542:G:GT	donor_gain	0.4800
4:150584378:C:CT	acceptor_gain	0.4800
4:150584680:A:AC	donor_gain	0.4700
4:150584681:C:CC	donor_gain	0.4700
4:150583268:TAA:T	donor_gain	0.4500
4:150583269:AAA:A	donor_gain	0.4500
4:150584229:TCCGG:T	acceptor_gain	0.4500
4:150584230:CCGGC:C	acceptor_gain	0.4500
4:150583051:CTGGT:C	donor_gain	0.4300
4:150583052:TGGTT:T	donor_gain	0.4300
4:150582448:GACAT:G	donor_gain	0.4200
4:150582956:C:CT	donor_gain	0.4000
4:150582421:GAC:G	donor_gain	0.3900
4:150582817:A:AG	acceptor_gain	0.3900
4:150582818:G:GG	acceptor_gain	0.3900
4:150584685:A:AC	donor_gain	0.3900

AlphaMissense

2331 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:150583154:T:C	L42P	1.000
4:150583174:G:A	E49K	1.000
4:150583180:C:A	R51S	1.000
4:150583180:C:G	R51G	1.000
4:150583277:T:C	M83T	1.000
4:150583279:G:C	G84R	1.000
4:150583279:G:T	G84C	1.000
4:150583328:T:A	L100H	1.000
4:150583328:T:C	L100P	1.000
4:150583330:A:G	K101E	1.000
4:150583332:A:C	K101N	1.000
4:150583332:A:T	K101N	1.000
4:150583334:T:A	L102Q	1.000
4:150583334:T:C	L102P	1.000
4:150583336:A:C	S103R	1.000
4:150583338:C:A	S103R	1.000
4:150583338:C:G	S103R	1.000
4:150583339:G:C	D104H	1.000
4:150583339:G:T	D104Y	1.000
4:150583340:A:C	D104A	1.000
4:150583340:A:T	D104V	1.000
4:150583348:A:G	K107E	1.000
4:150583350:G:C	K107N	1.000
4:150583350:G:T	K107N	1.000
4:150583354:A:C	S109R	1.000
4:150583355:G:T	S109I	1.000
4:150583356:C:A	S109R	1.000
4:150583356:C:G	S109R	1.000
4:150583358:T:A	M110K	1.000
4:150583359:G:A	M110I	1.000

dbSNP variants (sampled 300 via entrez): RS1000714817 (4:150581950 G>A,C), RS1000764437 (4:150584606 G>A), RS1001102796 (4:150581592 G>T), RS1002276043 (4:150581138 A>G), RS1002872585 (4:150582239 A>G), RS1002926419 (4:150582493 A>G), RS1003204803 (4:150583911 G>A,C), RS1003260189 (4:150584476 C>CG), RS1003651761 (4:150585053 A>T), RS1004161290 (4:150582145 C>T), RS1004171114 (4:150582542 G>C), RS1004858906 (4:150580304 T>A), RS1005171969 (4:150580482 T>C), RS1005181847 (4:150580761 A>C), RS1007479249 (4:150580384 G>A)

Disease associations

OMIM: gene MIM:604357 | disease phenotypes: MIM:614700, MIM:615877

GenCC curated gene-disease

Disease	Classification	Inheritance
colobomatous microphthalmia-rhizomelic dysplasia syndrome	Definitive	Autosomal dominant
syndromic microphthalmia	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
colobomatous microphthalmia-rhizomelic dysplasia syndrome	Definitive	AD

Mondo (3): combined immunodeficiency due to LRBA deficiency (MONDO:0013863), colobomatous microphthalmia-rhizomelic dysplasia syndrome (MONDO:0014380), syndromic microphthalmia (MONDO:0016073)

Orphanet (2): Syndromic autoimmune enteropathy due to LRBA deficiency (Orphanet:445018), Colobomatous microphthalmia-rhizomelic dysplasia syndrome (Orphanet:424099)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000343	Long philtrum
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000528	Anophthalmia
HP:0000568	Microphthalmia
HP:0000589	Coloboma
HP:0000629	Periorbital fullness
HP:0000639	Nystagmus
HP:0000647	Sclerocornea
HP:0000826	Precocious puberty
HP:0001126	Cryptophthalmos
HP:0001763	Pes planus
HP:0002342	Moderate intellectual disability
HP:0003577	Congenital onset
HP:0004691	2-3 toe syndactyly
HP:0005001	Recurrent patellar dislocation
HP:0008905	Rhizomelia
HP:0009918	Ectopia pupillae
HP:0011220	Prominent forehead
HP:0011939	3-4 finger cutaneous syndactyly

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	7
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	5
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Cytarabine	decreases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Toluene	decreases expression, increases methylation	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Acrylamide	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3Z2	SEES3-1V human MAB21L2, clone1	Embryonic stem cell	Male
CVCL_A3Z3	SEES3-1V human MAB21L2, clone2	Embryonic stem cell	Male
CVCL_A3Z4	SEES3-1V human MAB21L2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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