MAD1L1

Summary

MAD1L1 (mitotic arrest deficient 1 like 1, HGNC:6762) is a protein-coding gene on chromosome 7p22.3, encoding Mitotic spindle assembly checkpoint protein MAD1 (Q9Y6D9). Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate.

MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8379 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 68
• Clinical variants (ClinVar): 177 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_001013836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6762
Approved symbol	MAD1L1
Name	mitotic arrest deficient 1 like 1
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	HsMAD1, TXBP181, MAD1, PIG9, TP53I9
Ensembl gene	ENSG00000002822
Ensembl biotype	protein_coding
OMIM	602686
Entrez	8379

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 35 protein_coding, 13 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265854, ENST00000399654, ENST00000402746, ENST00000406869, ENST00000421113, ENST00000429625, ENST00000429779, ENST00000437877, ENST00000438959, ENST00000444373, ENST00000445959, ENST00000450235, ENST00000455998, ENST00000459731, ENST00000464742, ENST00000468372, ENST00000469871, ENST00000477172, ENST00000481633, ENST00000483165, ENST00000486340, ENST00000491858, ENST00000496548, ENST00000853791, ENST00000853792, ENST00000853793, ENST00000853794, ENST00000853795, ENST00000853796, ENST00000853797, ENST00000853798, ENST00000853799, ENST00000853800, ENST00000853801, ENST00000853802, ENST00000853803, ENST00000853804, ENST00000853805, ENST00000853806, ENST00000853807, ENST00000853808, ENST00000932271, ENST00000932272, ENST00000967143, ENST00000967144, ENST00000967146, ENST00000967148, ENST00000967149, ENST00000967150

RefSeq mRNA: 6 — MANE Select: NM_001013836 NM_001013836, NM_001013837, NM_001304523, NM_001304524, NM_001304525, NM_003550

CCDS: CCDS43539, CCDS78201

Canonical transcript exons

ENST00000265854 — 19 exons

Exon	Start	End
ENSE00000976254	2219332	2219456
ENSE00001088370	1980453	1980541
ENSE00001088371	2002065	2002121
ENSE00001562723	2232872	2232945
ENSE00001671509	2225410	2225550
ENSE00002228326	2229984	2230143
ENSE00003463318	2216157	2216287
ENSE00003587079	2215885	2215999
ENSE00003601702	2069194	2069338
ENSE00003622508	1936687	1936897
ENSE00003637714	2217962	2218043
ENSE00003648846	2014502	2014642
ENSE00003687358	2149152	2149238
ENSE00003784979	1898200	1898390
ENSE00003787516	2213212	2213273
ENSE00003787900	1957629	1957719
ENSE00003790892	2222575	2222754
ENSE00003910821	2230549	2230727
ENSE00003911986	1815795	1816228

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6810 / max 351.1609, expressed in 1801 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82476	6.3055	1722
82477	4.9121	1714
82462	4.7979	630
82458	0.7676	315
82461	0.3546	127
82459	0.2247	71
82474	0.1116	47
82460	0.0817	35
82475	0.0574	24
82463	0.0256	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.56	gold quality
right testis	UBERON:0004534	95.75	gold quality
left testis	UBERON:0004533	95.54	gold quality
testis	UBERON:0000473	94.72	gold quality
granulocyte	CL:0000094	94.65	gold quality
putamen	UBERON:0001874	93.87	gold quality
blood	UBERON:0000178	92.23	gold quality
right lobe of liver	UBERON:0001114	90.90	gold quality
caudate nucleus	UBERON:0001873	90.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.46	gold quality
primary visual cortex	UBERON:0002436	90.11	gold quality
spleen	UBERON:0002106	89.97	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.85	gold quality
leukocyte	CL:0000738	89.48	gold quality
monocyte	CL:0000576	89.25	gold quality
calcaneal tendon	UBERON:0003701	89.21	gold quality
liver	UBERON:0002107	88.47	gold quality
apex of heart	UBERON:0002098	88.39	gold quality
nucleus accumbens	UBERON:0001882	88.01	gold quality
skin of leg	UBERON:0001511	87.85	gold quality
zone of skin	UBERON:0000014	87.36	gold quality
substantia nigra	UBERON:0002038	87.01	gold quality
skeletal muscle tissue	UBERON:0001134	86.81	gold quality
skin of abdomen	UBERON:0001416	86.73	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.67	gold quality
ventricular zone	UBERON:0003053	86.60	gold quality
cortical plate	UBERON:0005343	86.59	gold quality
mucosa of transverse colon	UBERON:0004991	86.53	gold quality
right frontal lobe	UBERON:0002810	86.48	gold quality
stromal cell of endometrium	CL:0002255	86.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPG, HIF1A, MXD1, MYCN, STAT3, TP53

miRNA regulators (miRDB)

6 targeting MAD1L1, 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-513B-5P	99.99	69.96	2150
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-8078	98.32	65.73	361
HSA-MIR-4457	98.09	67.12	1274

Literature-anchored findings (GeneRIF, showing 40)

• Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant. (PMID:11980658)
• Hec1 was required for the recruitment of Mps1 kinase and Mad1/Mad2 complexes to kinetochores (PMID:12351790)
• a regulatory mechanism for the mitotic checkpoint in which MAD1 is inhibited by p53. (PMID:12876282)
• NEK2A interacts with MAD1 during spindle checkpoint signaling (PMID:14978040)
• Stable partial downregulation of the spindle checkpoint gene MAD1, which is observed in human cancer, leads to a functional inactivation of the spindle checkpoint resulting in gross aneuploidy (PMID:15782113)
• Chromophobe renal cell carcinoma presented underexpression of MAD1, and MAD2L2. (PMID:17333263)
• The MAD1 gene could be a candidate tumor suppressor gene, and the down-regulation of MAD1 expression may contribute to tumorigenesis in human stomach. (PMID:17674037)
• PRP4 is a spindle assembly checkpoint protein required for MAD1 localization to the kinetochores. (PMID:17998396)
• Existence of a symmetric Mad2 dimer with Mad1-assisted conformational activation in the spindle checkpoint. (PMID:18318601)
• These results suggest that MAD1 promoter genotype may be involved in tumor progression. Moreover, the loss of MAD1 protein expression may be related to the tumor recurrence after surgical resection of HCC. (PMID:18491369)
• mechanistic roles contributed by protein phosphorylation and Plk1 to the spindle assembly checkpoint activity of Mad1 (PMID:18922800)
• Tpr regulates Mad1-Mad2 proteins are regulated during the cell cycle and mitotic spindle checkpoint signaling. (PMID:18981471)
• the novel splicing variant MAD1beta may have functions different from those of MAD1alpha and may play opposing roles to MAD1alpha in mitotic checkpoint control in hepatocarcinogenesis. (PMID:19010891)
• The expression of hTERT mRNA and deletion of Mad1 protein are closely related to pathogenesis of lung cancer. (PMID:19224688)
• Mad1 recruits RBP2 to the hTERT promoter that, in turn, demethylates H3-K4, thereby contributing to a stable repression of the hTERT gene in normal or differentiated malignant cells. (PMID:19762557)
• These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer. (PMID:20516147)
• Suppression of telomerase activity mediated by PinX1 is involved in the Mad1/c-Myc pathway. (PMID:20544396)
• Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. (PMID:20624899)
• Nup153 levels regulate the localization of Mad1 during the metaphase/anaphase transition thereby affecting its phoshorylation status and in turn spindle checkpoint activity and mitotic exit (PMID:21327106)
• TGFbeta1 induced MAD1 expression by recruitment C/EBPalpha/beta heterodimers, SP1, and SMAD3 binding to promoter of the MAD1. (PMID:21345218)
• Data suggest a model in which chromosome biorientation errors, which recruit Mad1-Mad2 to kinetochores, may be signalled not only through Mad2, but also through the activity of widely conserved kinases, to ensure fidelity of cell division. (PMID:21394085)
• Mad2 requires association with Mad1 to adopt the closed conformation. The Mad1:C-Mad2 complex is regulated by p31comet-dependent ‘capping’. Mad1:C-Mad2 acts as a template to sustain the SAC. It challenges the distinction between SAC & mitotic timer. (PMID:21772247)
• RED is required for kinetochore localization of MAD1, mitotic progression, and activation of the spindle assembly checkpoint. (PMID:22351768)
• results indicate that CTD is a part of an extensive kinetochore-binding interface of Mad1, and rationalize graded kinetochore targeting of Mad1 during checkpoint signaling (PMID:22493223)
• These results suggest that levels of Mad1 must be tightly regulated to prevent aneuploidy and transformation and that Mad1 up-regulation may promote tumors and cause resistance to current therapies. (PMID:22778409)
• Mad1 expression is inversely related to miR-125b expression in oral SCC tissues. (PMID:23099851)
• The polymorphism MAD1 1673 G –> A affects SAC functionality, increasing the frequency of aneuploid cells. This polymorphism modifies the response to agents that alter the dynamics of microtubules in patients with ovarian cancer (PMID:23407047)
• These data indicate that hypoxia-induced Mad1 lowers doxorubicin-stimulated generation of reactive oxygen species through mitochondrial inhibition and subsequently contributes to tumor resistance to doxorubicin (PMID:23459071)
• MAD1L1 might be used as a prognostic biomarker for breast cancer and expression of MAD1L1 in nuclei is also a predict biomarker of contraindication to pacilitaxel treatment in breast cancer. (PMID:23860928)
• High mad-1 expression is associated with myelodysplastic syndrome. (PMID:24095110)
• Tpr is required for normal SAC response by stabilizing Mad1 and Mad2 before mitosis. (PMID:24344181)
• PRAP1 is a protein interacting partner of MAD1 and that PRAP1 is able to down-regulate MAD1 and suppress mitotic checkpoint signalling in hepatocellular carcinoma. (PMID:24374861)
• Mad1 is required for mitotic arrest even when C-Mad2 is artificially recruited to kinetochores. The C-terminal globular domain of Mad1 and conserved residues in this region are required for this unexpected function of Mad1. (PMID:24477933)
• Results show that Mad1-Mad2 must be targeted to nuclear pore complexes (NPCs) in order to produce the premitotic Cdc20 inhibitor, which ensures that anaphase and mitotic exit are robustly coupled to the establishment and correction of kinetochore-microtubule attachments. (PMID:24581499)
• Mad1, in addition to converting Mad2 to its active conformation, scaffolds formation of a higher-order mitotic checkpoint complex at kinetochores. (PMID:24637323)
• MAD1 kinetochore localization dictates the spindle assembly checkpoint in metaphase. (PMID:24695965)
• This article reviews Mad1 and Mad2 - structural and functional relationship with implication in genetic diseases, specifically in cancer. [review] (PMID:24724894)
• An important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis. (PMID:24728176)
• Here we demonstrate that the centromere protein CENP-I is required to generate a stable association of RZZ and Mad1 with kinetochores. (PMID:24862574)
• Mad1 has a role in secretion and cell migration. (PMID:25447996)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mad1l1	ENSDARG00000033852
mus_musculus	Mad1l1	ENSMUSG00000029554
rattus_norvegicus	Mad1l1	ENSRNOG00000001265
caenorhabditis_elegans		WBGENE00003160

Protein

Protein identifiers

Mitotic spindle assembly checkpoint protein MAD1 — Q9Y6D9 (reviewed: Q9Y6D9)

Alternative names: Mitotic arrest deficient 1-like protein 1, Mitotic checkpoint MAD1 protein homolog, Tax-binding protein 181

All UniProt accessions (6): Q9Y6D9, C9J9H5, C9JIR0, C9JJ38, C9JKI7, C9JX80

UniProt curated annotations — full annotation on UniProt →

Function. Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. Forms a heterotetrameric complex with the closed conformation form of MAD2L1 (C-MAD2) at unattached kinetochores during prometaphase, recruits an open conformation of MAD2L1 (O-MAD2) and promotes the conversion of O-MAD2 to C-MAD2, which ensures mitotic checkpoint signaling. Sequesters MAD2L1 in the cytoplasm preventing its function as an activator of the mitotic spindle assembly checkpoint (SAC) resulting in SAC impairment and chromosomal instability in hepatocellular carcinomas.

Subunit / interactions. Homodimer. Dimerizes via its N- and C- terminal regions. Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex. Interacts with the closed conformation form of MAD2L1 (C-MAD2) and open conformation form of MAD2L1 (O-MAD2). It is unclear whether MAD1L1 dimerization promotes the conversion of closed to open conformation of MAD2L1. Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer. Perturbation of the original MAD1L1-MAD2L1 structure by the spindle checkpoint may decrease MAD2L1 affinity for MAD1L1. CDC20 can compete with MAD1L1 for MAD2L1 binding, until the attachment and/or tension dampen the checkpoint signal, preventing further release of MAD2L1 on to CDC20. Also able to interact with the BUB1/BUB3 complex. Interacts with NEK2. Interacts with TTK. Interacts with TPR; the interactions occurs in a microtubule-independent manner. Interacts with IK. Interacts with the viral Tax protein. Interacts with PRAP1. Interacts with MAD2L1; this interaction leads to the cytoplasmic sequestration of MAD2L1. Interacts with PRAP1.

Subcellular location. Nucleus. Chromosome. Centromere. Kinetochore. Nucleus envelope. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle. Spindle pole Cytoplasm.

Tissue specificity. Expressed in hepatocellular carcinomas and hepatoma cell lines (at protein level). Expressed in hepatocellular carcinomas and hepatoma cell lines (at protein level).

Post-translational modifications. Phosphorylated; by BUB1. Become hyperphosphorylated in late S through M phases or after mitotic spindle damage. Phosphorylated; by TTK.

Disease relevance. Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition (MVA7) [MIM:620189] A form of mosaic variegated aneuploidy syndrome, a severe disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor and leukemia reported in several cases. MVA7 is an autosomal recessive form characterized by increased susceptibility to benign and malignant neoplasms beginning in early childhood. Affected individuals show dysmorphic facies and may have early developmental delay. The disease may be caused by variants affecting the gene represented in this entry. Defects in MAD1L1 are involved in the development and/or progression of various types of cancer.

Induction. Increased by p53/TP53.

Similarity. Belongs to the MAD1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y6D9-1	1, MAD1-alpha	yes
Q9Y6D9-3	2
Q9Y6D9-4	3, MAD1-beta

RefSeq proteins (6): NP_001013858, NP_001013859, NP_001291452, NP_001291453, NP_001291454, NP_003541 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008672	Mad1	Family

Pfam: PF05557

UniProt features (66 total): sequence variant 15, mutagenesis site 11, modified residue 9, helix 7, strand 7, region of interest 4, splice variant 3, sequence conflict 3, turn 3, chain 1, cross-link 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7B1F	X-RAY DIFFRACTION	1.75
4DZO	X-RAY DIFFRACTION	1.76
1GO4	X-RAY DIFFRACTION	2.05
7B1H	X-RAY DIFFRACTION	2.4
7B1J	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6D9-F1	81.78	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 214, 428, 598, 610, 634, 716, 61, 1, 16, 61

Mutagenesis-validated functional residues (11):

Position	Phenotype
1–485	defective dimerization. abolishes binding to the closed and open conformations of mad2l1. impairs mitotic checkpoint sig
79–82	loss of nuclear localization.
540–551	loss of interaction with mad2l1.
541	abolishes binding to closed and open conformations of mad2l1 and impairs mitotic checkpint signaling abolishing mitotic
543	abolishes binding to closed and open conformations of mad2l1 and impairs mitotic checkpoint signaling abolishing mitotic
597–718	defective dimerization. reduces binding to the closed and open conformations of mad2l1. impairs mitotic checkpoint signa
598	does not impact the duration of mitosis.
610	impairs mitotic checkpoint signaling and shortens the duration of mitosis.
634	reduces binding to closed and open conformations of mad2l1. impairs mitotic checkpoint signaling abolishing mitotic arre
634	reduces binding to closed and open conformations of mad2l1. does not impact the duration of mitosis.
716	reduces binding to closed and open conformations of mad2l1. impairs mitotic checkpoint signaling and shortens the durati

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-141424	Amplification of signal from the kinetochores
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69618	Mitotic Spindle Checkpoint
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 381 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_THYMUS_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, LANG_MYB_FAMILY_TARGETS

GO Biological Process (9): mitotic spindle assembly checkpoint signaling (GO:0007094), negative regulation of T cell proliferation (GO:0042130), thymus development (GO:0048538), cell division (GO:0051301), attachment of mitotic spindle microtubules to kinetochore (GO:0051315), regulation of metaphase plate congression (GO:0090235), positive regulation of mitotic cell cycle spindle assembly checkpoint (GO:0090267), deactivation of mitotic spindle assembly checkpoint (GO:1902426), regulation of mitotic cell cycle phase transition (GO:1901990)

GO Molecular Function (3): identical protein binding (GO:0042802), kinetochore binding (GO:0043515), protein binding (GO:0005515)

GO Cellular Component (16): kinetochore (GO:0000776), spindle pole (GO:0000922), nucleus (GO:0005634), nuclear envelope (GO:0005635), cytoplasm (GO:0005737), centrosome (GO:0005813), spindle (GO:0005819), cytosol (GO:0005829), nuclear pore nuclear basket (GO:0044615), mitotic spindle (GO:0072686), MAD1 complex (GO:1990706), mitotic spindle assembly checkpoint MAD1-MAD2 complex (GO:1990728), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694), cytoskeleton (GO:0005856), mitotic spindle pole (GO:0097431)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Mitotic Prometaphase	2
M Phase	2
Cell Cycle	2
Amplification of signal from the kinetochores	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
Mitotic Spindle Checkpoint	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle Checkpoints	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	4
cellular anatomical structure	3
binding	2
spindle	2
cytoplasm	2
protein-containing complex	2
mitotic cell cycle	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
hematopoietic or lymphoid organ development	1
gland development	1
cellular process	1
mitotic metaphase chromosome alignment	1
attachment of spindle microtubules to kinetochore	1
mitotic cell cycle process	1
regulation of localization	1
metaphase chromosome alignment	1
mitotic spindle assembly checkpoint signaling	1
positive regulation of cell cycle process	1
positive regulation of spindle checkpoint	1
regulation of mitotic cell cycle spindle assembly checkpoint	1
negative regulation of mitotic spindle assembly checkpoint signaling	1
regulation of mitotic cell cycle	1
mitotic cell cycle phase transition	1
regulation of cell cycle phase transition	1
protein binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1

Protein interactions and networks

STRING

2352 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAD1L1	MAD2L1	Q13257	987
MAD1L1	BUB1B	O60566	855
MAD1L1	CDC20	Q12834	721
MAD1L1	BUB3	O43684	678
MAD1L1	PCID2	Q5JVF3	670
MAD1L1	TSNARE1	Q96NA8	655
MAD1L1	BUB1	O43683	642
MAD1L1	CCNB1	P14635	636
MAD1L1	TRANK1	O15050	624
MAD1L1	BRCA2	P51587	605
MAD1L1	MRM2	Q9UI43	578
MAD1L1	RFWD3	Q6PCD5	578
MAD1L1	MAD2L1BP	Q15013	565
MAD1L1	CDC23	Q9UJX2	552
MAD1L1	TTK	P33981	543

IntAct

350 interactions, top by confidence:

A	B	Type	Score
MAD1L1	MAD2L1	psi-mi:“MI:0407”(direct interaction)	0.980
MAD2L1	CDC20	psi-mi:“MI:0914”(association)	0.980
MAD2L1	MAD1L1	psi-mi:“MI:0407”(direct interaction)	0.980
MAD1L1	MAD2L1	psi-mi:“MI:0914”(association)	0.980
MAD1L1	MAD2L1	psi-mi:“MI:0915”(physical association)	0.980
MAD2L1	MAD1L1	psi-mi:“MI:0915”(physical association)	0.980
MAD2L1	MAD1L1	psi-mi:“MI:2364”(proximity)	0.980
MAD2L1	MAD2L1	psi-mi:“MI:0914”(association)	0.890
MAD1L1	BAG5	psi-mi:“MI:0915”(physical association)	0.870
BAG5	MAD1L1	psi-mi:“MI:0915”(physical association)	0.870
TPM3	MAD1L1	psi-mi:“MI:0915”(physical association)	0.850
MAD1L1	TPM3	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (245): MAD1L1 (Two-hybrid), MAD1L1 (Two-hybrid), MAD1L1 (Two-hybrid), MAD1L1 (Two-hybrid), MAD1L1 (Two-hybrid), MAD1L1 (Two-hybrid), RNF8 (Two-hybrid), BAG5 (Two-hybrid), SPATA2 (Two-hybrid), USP15 (Two-hybrid), NEBL (Two-hybrid), TRIM29 (Two-hybrid), LGALSL (Two-hybrid), CCHCR1 (Two-hybrid), ZSCAN32 (Two-hybrid)

ESM2 similar proteins: A0PJP4, A0PJT0, A1A600, A2A6T1, A4IFK7, D3YV10, D3ZUQ0, G9G127, P97817, Q08379, Q0IHE5, Q0P4J3, Q17QG3, Q499E4, Q5EBL4, Q5RCR6, Q5RD32, Q5VU43, Q5XIA0, Q5XJA2, Q5ZJA3, Q61043, Q62839, Q6AYA0, Q6DFC2, Q6IP02, Q6NZT2, Q80YF0, Q86X02, Q86YS3, Q8BH60, Q8BQP8, Q8C2K1, Q8IYE1, Q8N4C6, Q91WG2, Q921M4, Q92574, Q969X0, Q96CN9

Diamond homologs: Q80YF0, Q9WTX8, Q9Y6D9, Q9LTY1

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
TPR	up-regulates	MAD1L1	binding
MAX	“up-regulates activity”	MAD1L1	binding
RPS6KA3	“up-regulates activity”	MAD1L1
ATM	“up-regulates activity”	MAD1L1	phosphorylation
CENPE	“up-regulates activity”	MAD1L1
BUB1	“up-regulates activity”	MAD1L1	relocalization
PLK1	“up-regulates activity”	MAD1L1	phosphorylation
TTK	“up-regulates activity”	MAD1L1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	123
Likely benign	12
Benign	4

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2443777	NM_001013836.2(MAD1L1):c.196C>T (p.Gln66Ter)	Pathogenic
2443778	NM_001013836.2(MAD1L1):c.1882G>T (p.Glu628Ter)	Pathogenic
2576570	NM_001013836.2(MAD1L1):c.820_823del (p.Glu274fs)	Pathogenic
2576571	NM_001013836.2(MAD1L1):c.1396C>T (p.Gln466Ter)	Pathogenic
6919	NM_001013836.2(MAD1L1):c.1947C>G (p.Tyr649Ter)	Pathogenic
4690248	NM_001013836.2(MAD1L1):c.244C>T (p.Arg82Ter)	Likely pathogenic

SpliceAI

11677 predictions. Top by Δscore:

Variant	Effect	Δscore
7:1816229:C:CG	acceptor_loss	1.0000
7:1816230:T:A	acceptor_loss	1.0000
7:1816238:A:T	acceptor_gain	1.0000
7:1816241:C:CT	acceptor_gain	1.0000
7:1816242:A:T	acceptor_gain	1.0000
7:1898386:CAGCT:C	acceptor_gain	1.0000
7:1898387:AGCT:A	acceptor_gain	1.0000
7:1898388:GCT:G	acceptor_gain	1.0000
7:1898389:CT:C	acceptor_gain	1.0000
7:1898389:CTC:C	acceptor_gain	1.0000
7:1898390:TCT:T	acceptor_gain	1.0000
7:1898391:C:CC	acceptor_gain	1.0000
7:1898391:C:CG	acceptor_loss	1.0000
7:1898391:C:T	acceptor_gain	1.0000
7:1898395:G:T	acceptor_gain	1.0000
7:1936683:CTACC:C	donor_loss	1.0000
7:1936684:TACCT:T	donor_loss	1.0000
7:1936685:A:C	donor_loss	1.0000
7:1936686:C:G	donor_loss	1.0000
7:1936686:CCTG:C	donor_gain	1.0000
7:1936687:CTGC:C	donor_gain	1.0000
7:1936688:TGCC:T	donor_gain	1.0000
7:1936695:T:TA	donor_gain	1.0000
7:1936893:TCACC:T	acceptor_gain	1.0000
7:1936894:CACC:C	acceptor_gain	1.0000
7:1936894:CACCC:C	acceptor_gain	1.0000
7:1936895:ACC:A	acceptor_gain	1.0000
7:1936896:CC:C	acceptor_gain	1.0000
7:1936896:CCC:C	acceptor_gain	1.0000
7:1936897:CC:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000005721 (7:2142317 CA>C), RS1000008033 (7:2074839 G>A), RS1000009541 (7:2155022 G>A,T), RS1000018048 (7:1998487 C>A,T), RS1000023475 (7:2052404 G>C), RS1000024958 (7:1939876 G>T), RS1000028327 (7:1936044 G>A,C,T), RS1000042934 (7:2083031 G>A), RS1000047895 (7:2084976 A>G), RS1000050742 (7:2231710 A>G), RS1000051661 (7:2204242 C>A,G), RS1000051727 (7:1886511 T>C), RS1000060715 (7:1963378 G>A,T), RS1000063001 (7:2178552 G>C), RS1000064833 (7:2142519 G>A)

Disease associations

OMIM: gene MIM:602686 | disease phenotypes: MIM:620189, MIM:257300

GenCC curated gene-disease

Disease	Classification	Inheritance
mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition	Limited	Autosomal recessive
familial prostate carcinoma	Limited	Unknown

Mondo (4): mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition (MONDO:0859346), mosaic variegated aneuploidy syndrome 1 (MONDO:0009759), prostate cancer (MONDO:0008315), familial prostate carcinoma (MONDO:0023122)

Orphanet (2): Mosaic variegated aneuploidy syndrome (Orphanet:1052), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000490	Deeply set eye
HP:0000639	Nystagmus
HP:0000962	Hyperkeratosis
HP:0001263	Global developmental delay
HP:0001442	Typified by somatic mosaicism
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0003764	Nevus
HP:0005701	Multiple enchondromatosis
HP:0005987	Multinodular goiter
HP:0006743	Embryonal rhabdomyosarcoma
HP:0011463	Childhood onset
HP:0011800	Midface retrusion
HP:0012032	Lipoma
HP:0012125	Prostate cancer
HP:0030079	Cervix cancer
HP:0030434	Pilomatrixoma
HP:0040276	Adenocarcinoma of the colon

GWAS associations

68 associations (top):

Study	Trait	p-value
GCST000785_15	Longevity	1.000000e-06
GCST001241_17	Bipolar disorder	7.000000e-06
GCST001565_9	Schizophrenia	2.000000e-09
GCST002023_6	Testicular germ cell tumor	6.000000e-09
GCST002149_3	Schizophrenia	6.000000e-13
GCST002254_4	Schizophrenia, schizoaffective disorder or bipolar disorder	6.000000e-10
GCST002295_10	Schizophrenia or bipolar disorder	2.000000e-06
GCST002295_2	Schizophrenia or bipolar disorder	2.000000e-09
GCST003724_3	Bipolar disorder	8.000000e-12
GCST003830_57	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	2.000000e-06
GCST004139_10	Bipolar disorder	4.000000e-07
GCST004139_21	Bipolar disorder	2.000000e-09
GCST004521_24	Autism spectrum disorder or schizophrenia	2.000000e-11
GCST004521_264	Autism spectrum disorder or schizophrenia	7.000000e-16
GCST004635_16	Testicular germ cell tumor	6.000000e-13
GCST004713_24	Testicular germ cell tumor	2.000000e-10
GCST004946_88	Schizophrenia	4.000000e-17
GCST005194_234	Coronary artery disease	4.000000e-06
GCST005195_89	Coronary artery disease	2.000000e-08
GCST005196_143	Coronary artery disease	5.000000e-09
GCST005759_5	Dimensional psychopathology (Social)	2.000000e-07
GCST005790_73	Rosacea symptom severity	8.000000e-06
GCST005829_26	Hand grip strength	3.000000e-09
GCST005830_102	Hand grip strength	8.000000e-12
GCST006083_2	Prostate cancer (advanced)	3.000000e-07
GCST006085_86	Prostate cancer	5.000000e-08
GCST006803_2	Schizophrenia	1.000000e-18
GCST007201_275	Schizophrenia	1.000000e-13
GCST007201_68	Schizophrenia	2.000000e-15
GCST007267_316	Systolic blood pressure	5.000000e-09

EFO canonical traits (24, from GWAS)

EFO ID	Trait name
EFO:0005921	FEV change measurement
EFO:0009100	social domain measurement
EFO:0009180	rosacea severity measurement
EFO:0006941	grip strength measurement
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0009749	age at first sexual intercourse measurement
EFO:0004324	body weights and measures
EFO:0007660	neuroticism measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0009658	adverse effect
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0009863	anxiety measurement
EFO:0011013	vaginal microbiome measurement
EFO:0004352	mortality
EFO:0005670	smoking initiation
EFO:0009101	age at first birth measurement
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1801368	Efficacy	3	carboplatin;paclitaxel	Ovarian Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801368	MAD1L1	3	0.75	1	carboplatin;paclitaxel

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	7
Aflatoxin B1	affects expression, affects methylation, decreases expression	5
bisphenol A	affects methylation, affects cotreatment, decreases expression, increases expression	3
Air Pollutants	increases oxidation, affects expression, increases expression, affects cotreatment, increases abundance	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
bisphenol S	affects expression, decreases methylation	2
Cisplatin	decreases expression	2
Estradiol	increases expression, affects binding	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
Quercetin	decreases expression, increases expression	2
Smoke	increases abundance, increases expression, decreases expression	2
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
sotorasib	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
ethylene dichloride	increases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
1-hydroxypyrene	affects cotreatment, increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7D7	Abcam A-549 MAD1L1 KO	Cancer cell line	Male
CVCL_C7DX	Abcam HCT 116 MAD1L1 KO	Cancer cell line	Male
CVCL_C7EK	Abcam THP-1 MAD1L1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer