MLXIPL

Summary

MLXIPL (MLX interacting protein like, HGNC:12744) is a protein-coding gene on chromosome 7q11.23, encoding Carbohydrate-responsive element-binding protein (Q9NP71). Glucose-responsive transcription activator that regulates fatty acid synthesis and glycolysis.

This gene encodes a basic helix-loop-helix leucine zipper transcription factor of the Myc/Max/Mad superfamily. This protein forms a heterodimeric complex and binds and activates, in a glucose-dependent manner, carbohydrate response element (ChoRE) motifs in the promoters of triglyceride synthesis genes. The gene is deleted in Williams-Beuren syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51085 — RefSeq curated summary.

At a glance

• GWAS associations: 165
• Clinical variants (ClinVar): 213 total — 1 pathogenic
• Phenotypes (HPO): 107
• Transcription factor: yes — 18 downstream targets (CollecTRI)
• MANE Select transcript: NM_032951

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12744
Approved symbol	MLXIPL
Name	MLX interacting protein like
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	WS-bHLH, MIO, CHREBP, MONDOB, bHLHd14
Ensembl gene	ENSG00000009950
Ensembl biotype	protein_coding
OMIM	605678
Entrez	51085

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000313375, ENST00000345114, ENST00000354613, ENST00000414749, ENST00000429400, ENST00000434326, ENST00000453275, ENST00000456640, ENST00000467221, ENST00000476404, ENST00000488212, ENST00000855640, ENST00000855641, ENST00000855642, ENST00000855643, ENST00000855644, ENST00000855645, ENST00000855646, ENST00000855647, ENST00000855648, ENST00000855649, ENST00000855650, ENST00000855651, ENST00000855652, ENST00000855653, ENST00000855654

RefSeq mRNA: 4 — MANE Select: NM_032951 NM_032951, NM_032952, NM_032953, NM_032954

CCDS: CCDS47605, CCDS47606, CCDS5553, CCDS5554

Canonical transcript exons

ENST00000313375 — 17 exons

Exon	Start	End
ENSE00000977118	73607590	73607672
ENSE00000977119	73607331	73607420
ENSE00000977120	73606974	73607018
ENSE00001231954	73596639	73596789
ENSE00001611637	73616071	73616177
ENSE00003470920	73596153	73596272
ENSE00003514137	73596364	73596479
ENSE00003533239	73597182	73597713
ENSE00003549646	73599526	73599695
ENSE00003606485	73595637	73595760
ENSE00003618110	73594274	73594403
ENSE00003620721	73605688	73605768
ENSE00003642626	73595842	73595969
ENSE00003643514	73596865	73596932
ENSE00003787671	73605910	73606111
ENSE00003844757	73624200	73624522
ENSE00003846036	73593202	73593983

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 99.50.

FANTOM5 (CAGE): breadth broad, TPM avg 6.0602 / max 419.5703, expressed in 631 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84311	4.8656	574
84313	0.6785	244
84314	0.3900	191
84312	0.1261	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.50	gold quality
right adrenal gland	UBERON:0001233	97.82	gold quality
left adrenal gland cortex	UBERON:0035825	97.82	gold quality
right adrenal gland cortex	UBERON:0035827	97.82	gold quality
left adrenal gland	UBERON:0001234	97.58	gold quality
adrenal cortex	UBERON:0001235	97.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.36	gold quality
cerebellar hemisphere	UBERON:0002245	95.98	gold quality
cerebellar cortex	UBERON:0002129	95.92	gold quality
omental fat pad	UBERON:0010414	94.91	gold quality
peritoneum	UBERON:0002358	94.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.39	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.24	gold quality
cerebellum	UBERON:0002037	94.12	gold quality
liver	UBERON:0002107	94.05	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.02	gold quality
mucosa of stomach	UBERON:0001199	93.90	gold quality
gastrocnemius	UBERON:0001388	93.24	gold quality
right testis	UBERON:0004534	93.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.78	gold quality
left testis	UBERON:0004533	92.24	gold quality
small intestine	UBERON:0002108	92.05	gold quality
adipose tissue	UBERON:0001013	91.99	gold quality
adrenal gland	UBERON:0002369	91.63	gold quality
muscle of leg	UBERON:0001383	91.27	gold quality
right frontal lobe	UBERON:0002810	90.40	gold quality
body of pancreas	UBERON:0001150	90.30	gold quality
connective tissue	UBERON:0002384	90.26	gold quality
right uterine tube	UBERON:0001302	89.89	gold quality
type B pancreatic cell	CL:0000169	89.79	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	1984.65
E-GEOD-130473	yes	761.81
E-GEOD-125970	yes	15.95
E-ANND-3	yes	15.42
E-GEOD-81547	yes	10.30
E-GEOD-83139	yes	9.75
E-CURD-135	no	830.36
E-HCAD-31	no	18.84

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

18 targets.

Target	Regulation
ACACA	Activation
ARNT	Unknown
CREBBP	Unknown
ELOVL6	Activation
FAS	Activation
FASN	Unknown
FGF21	Unknown
GCGR	Unknown
KHK	Repression
KLF10
PKLR	Unknown
PNPLA3	Unknown
PPARA	Unknown
PPARG	Activation
SLC2A4
SLU7
TRIB3
TXNIP	Activation

JASPAR motifs

Motif	Name	Family
MA0664.1	MLXIPL	bHLH-ZIP
MA0664.2	MLXIPL	bHLH-ZIP

JASPAR matrix evidence (PMIDs): PMID:14742444

Upstream regulators (CollecTRI, top): FOXA1, FOXA2, MAX, MYC, NR1H3, POU2F1, SREBF1, THRB

miRNA regulators (miRDB)

30 targeting MLXIPL, 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-8485	100.00	77.57	4731
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-6815-5P	96.05	65.55	662
HSA-MIR-6865-5P	96.05	65.58	675
HSA-MIR-6889-5P	90.26	64.13	291
HSA-MIR-6777-5P	88.76	62.64	222

Literature-anchored findings (GeneRIF, showing 40)

• This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation. (PMID:16644671)
• Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. (PMID:18193046)
• Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity.( (PMID:18591247)
• Phosphorylation of ChREBP was essential for its interaction with CRM1 for export to the cytosol, whereas nuclear import of ChREBP requires dephosphorylated ChREBP to interact with importin alpha. (PMID:18606808)
• tested the hypothesis that the MLXIPL rs3812316 variant predicts plasma triglyceride (TG) levels. We found no difference between individuals with high TG and controls, and no association between the variant and plasma TG levels among the controls (PMID:18946681)
• The transcription factor ChRepsilonBP is a major mediator of glucose action on lipogenic genes & a key determinant of lipid synthesis in vitro. Review. (PMID:18950580)
• we were not able to find any statistically significant association between the single nucleotide polymorphisms in the FAS, ChREBP and SREPB-1 genes and an increased risk of breast cancer (PMID:19252981)
• G771C polymorphism significantly related to coronary artery disease in Chinese patients (PMID:19571538)
• suppression of ChREBP led to a p53-dependent reduction in tumor growth. These results demonstrate that ChREBP plays a key role both in redirecting glucose metabolism to anabolic pathways and suppressing p53 activity (PMID:19995986)
• a new nuclear export signal site (“NES1”) of ChREBP was reported. (PMID:20025850)
• These results suggest that the O-linked glycosylation of ChREBP itself or other proteins that regulate ChREBP is essential for the production of functional ChREBP. (PMID:21036147)
• in immortalized hepatocytes and in HepG2 hepatoma cells, only SREBP1c was able to induce adiponutrin/PNPLA3 expression, whereas ChREBP was unable to modulate its expression (PMID:21145868)
• ChREBP is a critical and direct mediator of glucose repression of PPARalpha gene expression in pancreatic beta-cells (PMID:21282101)
• an important mechanism by which importin-alpha and 14-3-3 control movement of ChREBP in and out of the nucleus in response to changes in glucose levels in liver (PMID:21665952)
• The rs3812316 and the haplotypes in ChREBP gene appeared to be related to high susceptibility to CAD (PMID:21726544)
• ChREBP may function as a transcriptional repressor as well as an activator. (PMID:21811631)
• Our study reports that PP2A activity is dispensable for ChREBP activation in response to glucose and that dephosphorylation on Ser-196 is not sufficient to promote ChREBP nuclear translocation in the absence of a rise in glucose metabolism. (PMID:21835137)
• The dramatic increase of ChREBP mRNA and protein levels during preadipocyte differentiation suggests a role in adipogenesis. (PMID:21840420)
• Multiple linear regression models based on 2373 individuals of Asian origin showed that the H allele of the MLXIPL gene was significantly associated with decreased concentrations of plasma triglycerides. (PMID:21938000)
• sorcin retains ChREBP in the cytosol at low glucose concentrations and may act as a Ca(2+) sensor for glucose-induced nuclear translocation and the activation of ChREBP-dependent genes. (PMID:22338092)
• ChREBP-beta expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes. (PMID:22466288)
• ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs (PMID:22546860)
• Data from obese adolescents with prediabetes/early type 2 diabetes suggest that expression of ChREBP-alpha/beta in abdominal subcutaneous adipose tissue is inversely related to hyperglycemia severity and positively correlated to insulin resistance. (PMID:23209190)
• de novo lipogenesis predicts metabolic health in humans in a tissue-specific manner and is likely regulated by glucose-dependent carbohydrate-responsive element-binding protein activation. (PMID:23443556)
• Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes. (PMID:23530060)
• Data suggest that CHREBP is a central regulator of glycolysis/lipogenesis in liver and apoptosis/proliferation in specific cell types. [REVIEW] (PMID:23597489)
• Data suggest that the activity of CHREBP is regulated via various mechanisms and that CHREBP is involved in the modulation of glucose and lipid metabolism in liver, pancreatic beta-cells, and adipose tissue. [REVIEW] (PMID:23604004)
• FOXO1 inhibits beta cell TXNIP transcription and suggest that FOXO1 confers this inhibition by interfering with ChREBP DNA binding at target gene promoters. (PMID:23803610)
• FLII is a component of the ChREBP transcriptional complex and negatively regulates ChREBP function in cancer cells. (PMID:24055811)
• The ChREBP expression may be reflective of an aerobic metabolic phenotype that may conflict with hypoxia-induced signalling but provide a mechanism for growth at the oxygenated edge of the tumours. (PMID:24366300)
• The MLXIPL-rs3812316 was associated with lower baseline triglycerides and lower hypertriglyceridemia. (PMID:24448738)
• ChREBP plays a key role in reprogramming glucose and lipid metabolism in human cytomegalovirus infection. (PMID:24449882)
• The ChREBP mutant, W130A, did not exhibit HG-induced lipid accumulation and fibrotic proteins, suggesting that the Trp-130 residue in the MCR3 domain is important in the development of glomerulosclerosis. (PMID:24616092)
• High glucose-induced, ChREBP-mediated, and normoxic HIF-1alpha activation that may be partially responsible for neovascularization in both diabetic and age-related retinopathy. (PMID:24664750)
• demonstrates that Chrebp interacts with AR and regulates its transcriptional activity (PMID:24845031)
• Significant linkage disequilibria were noted among ZNF259, BUD13 and MLXIPL SNPs and serum lipid levels. (PMID:24989072)
• results demonstrate that AGEs-RAGE signaling enhances cancer cell proliferation in which AGEs-mediated ChREBP induction plays an important role. (PMID:25111846)
• Single-nucleotide polymorphisms alleles near MLXIPL that were associated with higher coffee consumption. (PMID:25288136)
• Polymorphisms in lipid level modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 genes are highly associated with plasma lipid level changes. (PMID:25573592)
• A major function of Mio in mitosis is to regulate the activation/deactivation of Plk1 and Aurora A. (PMID:26124292)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000089107
danio_rerio	mlxipl	ENSDARG00000104054
mus_musculus	Mlxipl	ENSMUSG00000005373
rattus_norvegicus	AABR07035839.1	ENSRNOG00000046171
drosophila_melanogaster	Mondo	FBGN0032940
caenorhabditis_elegans		WBGENE00003378

Paralogs (3): TFAP4 (ENSG00000090447), MLX (ENSG00000108788), MLXIP (ENSG00000175727)

Protein

Protein identifiers

Carbohydrate-responsive element-binding protein — Q9NP71 (reviewed: Q9NP71)

Alternative names: Class D basic helix-loop-helix protein 14, MLX interactor, MLX-interacting protein-like, WS basic-helix-loop-helix leucine zipper protein, Williams-Beuren syndrome chromosomal region 14 protein

All UniProt accessions (4): Q9NP71, A0A0C4DG26, C9JDF5, H7C1V3

UniProt curated annotations — full annotation on UniProt →

Function. Glucose-responsive transcription activator that regulates fatty acid synthesis and glycolysis. Key determinant of systemic insulin sensitivity and glucose homeostasis. Important for the expression of fatty acid synthetic enzymes, including PC/Pcx, APOC4/Acl, ACACA/Acc1 and FASN/Fas. Important for glucose-induced expression of L-type pyruvate kinase/PKLR. Binds to the canonical and non-canonical E box DNA sequences 5’-CACGTG-3’ and 5’-CACGCG-3’. May also act as a transcriptional repressor.

Subunit / interactions. Binds DNA as a heterodimer with MLX/TCFL4.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed with high levels in heart, brain, placenta, skeletal muscle and pancreas. Also expressed in fetal kidney, lung, liver and brain. Expressed in fetal and adult liver. Expressed in the cerebral cortex, including in the frontal, temporal, parietal and occipital lobes, and the cerebellum. Also detected in the intestine, including jejunum, ileum and colon.

Post-translational modifications. Phosphorylation at Ser-556 by AMPK inactivates the DNA-binding activity.

Disease relevance. WBSCR14 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of WBSCR14 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. In non-diabetic individuals with normal glucose tolerance and widely ranging body mass index values, expression in subcutaneous white adipose tissue correlates strongly with insulin sensitivity measured during a euglycemic and hyperinsulinaemic clamp procedure. In non-diabetic obese individuals, adipose expression is directly associated with insulin-stimulated glucose uptake during a clamp, independent of body mass index.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9NP71-1	1, Alpha	yes
Q9NP71-2	2, Beta
Q9NP71-3	3, Gamma
Q9NP71-4	4, Delta
Q9NP71-5	5, Epsilon
Q9NP71-6	6

RefSeq proteins (4): NP_116569, NP_116570, NP_116571, NP_116572 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR052207	Max-like/E-box_TFs	Family

Pfam: PF00010

UniProt features (33 total): modified residue 10, splice variant 7, region of interest 6, compositionally biased region 4, sequence variant 2, chain 1, domain 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8BTQ	X-RAY DIFFRACTION	1.6
8C1Y	X-RAY DIFFRACTION	1.8
8BWE	X-RAY DIFFRACTION	2
6YGJ	X-RAY DIFFRACTION	2.07
8BWH	X-RAY DIFFRACTION	2.1
6MJL	X-RAY DIFFRACTION	2.5
9GCP	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP71-F1	54.95	0.16

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): 20, 23, 25, 27, 29, 196, 556, 602, 614, 631

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-163358	PKA-mediated phosphorylation of key metabolic factors
R-HSA-163680	AMPK inhibits chREBP transcriptional activation activity
R-HSA-163765	ChREBP activates metabolic gene expression
R-HSA-163767	PP2A-mediated dephosphorylation of key metabolic factors
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism

MSigDB gene sets: 0 (showing top):

GO Biological Process (21): positive regulation of transcription from RNA polymerase II promoter by glucose (GO:0000432), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell population proliferation (GO:0008284), lipid biosynthetic process (GO:0008610), anatomical structure morphogenesis (GO:0009653), glucose mediated signaling pathway (GO:0010255), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), glucose homeostasis (GO:0042593), positive regulation of fatty acid biosynthetic process (GO:0045723), positive regulation of glycolytic process (GO:0045821), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of lipid biosynthetic process (GO:0046889), fatty acid homeostasis (GO:0055089), triglyceride homeostasis (GO:0070328), negative regulation of oxidative phosphorylation (GO:0090324), energy homeostasis (GO:0097009), negative regulation of signal transduction by p53 class mediator (GO:1901797), negative regulation of transcription by RNA polymerase II (GO:0000122)

GO Molecular Function (12): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), carbohydrate response element binding (GO:0035538), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA-binding transcription factor binding (GO:0140297), protein dimerization activity (GO:0046983)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Integration of energy metabolism	4
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	4
DNA-templated transcription	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
DNA-binding transcription factor activity	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
regulation of transcription from RNA polymerase II promoter by glucose	1
carbon catabolite activation of transcription from RNA polymerase II promoter	1
positive regulation of transcription by glucose	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
lipid metabolic process	1
biosynthetic process	1
developmental process	1
anatomical structure development	1
hexose mediated signaling	1
cellular response to glucose stimulus	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
carbohydrate homeostasis	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
positive regulation of fatty acid metabolic process	1
positive regulation of lipid biosynthetic process	1
glycolytic process	1
regulation of glycolytic process	1
positive regulation of purine nucleotide catabolic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of ATP metabolic process	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
lipid biosynthetic process	1

Protein interactions and networks

STRING

1588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLXIPL	MXD4	Q14582	931
MLXIPL	MLXIP	Q9HAP2	929
MLXIPL	SREBF1	P36956	894
MLXIPL	LIPE	Q05469	892
MLXIPL	TBL2	Q9Y4P3	885
MLXIPL	PKLR	P11973	808
MLXIPL	INSIG2	Q9Y5U4	772
MLXIPL	EP300	Q09472	749
MLXIPL	ACACA	Q13085	748
MLXIPL	FASN	P49327	741
MLXIPL	MNT	Q99583	729
MLXIPL	SCD	O00767	729
MLXIPL	INS	P01308	724
MLXIPL	PPARA	Q07869	723
MLXIPL	BCL7B	Q9BQE9	714

IntAct

12 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
MLXIPL	GRB2	psi-mi:“MI:0915”(physical association)	0.370
MLX	MLXIPL	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
MLX	BACH1	psi-mi:“MI:0914”(association)	0.350
MLX	MGA	psi-mi:“MI:0914”(association)	0.350
EVC2	SLC33A1	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (59): MLXIPL (Affinity Capture-Western), MLXIPL (Proximity Label-MS), MLXIPL (Affinity Capture-MS), MLXIPL (Affinity Capture-MS), MLXIPL (Affinity Capture-MS), MLXIPL (Affinity Capture-MS), MLXIPL (Affinity Capture-MS), SMURF2 (Affinity Capture-Western), SMURF2 (Co-localization), MLXIPL (Negative Genetic), MLXIPL (Affinity Capture-RNA), MLXIPL (Affinity Capture-MS), MLXIPL (Affinity Capture-MS), DDB1 (Affinity Capture-MS), Ddb1 (Affinity Capture-Western)

ESM2 similar proteins: A0PJX4, A2A8U2, A4D2P6, A6QM06, D4A6L0, E1BBQ2, O15079, O60320, P12755, P49797, P97260, Q0D2I5, Q12770, Q15884, Q1RMB5, Q3TS39, Q3UPR0, Q4FZH1, Q5MNU5, Q5SNT2, Q5T848, Q5XKK7, Q60698, Q6A044, Q7T0Z7, Q7TMB0, Q7TPB0, Q810F0, Q86XR5, Q8BX43, Q8BXL9, Q8C419, Q8CA71, Q8K064, Q8K2Y3, Q8N114, Q8NDY8, Q8WV15, Q91WM6, Q92537

Diamond homologs: O08609, Q2VPU4, Q8VIP2, Q99MZ3, Q9HAP2, Q9NP71, Q9UH92, P41846, Q9TZ70, D2CLZ9, O13126, P34474, P97831, Q01664, Q10574, Q8WVJ9, Q9D030

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
PRKAA1	down-regulates	MLXIPL	phosphorylation
MLXIPL	“up-regulates quantity by expression”	ELOVL6	“transcriptional regulation”
SIK2	down-regulates	MLXIPL
MLXIPL	“up-regulates quantity by expression”	ACACA	“transcriptional regulation”
MLXIPL	“up-regulates quantity by expression”	FAS	“transcriptional regulation”
AMPK	down-regulates	MLXIPL	phosphorylation
14-3-3	“down-regulates activity”	MLXIPL	relocalization
AMP	“down-regulates activity”	MLXIPL	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
G2/M DNA damage checkpoint	5	50.1×	9e-07
Signaling by Rho GTPases	5	14.2×	1e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	5	13.9×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	121
Likely benign	40
Benign	17

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
441785	GRCh37/hg19 7q11.23(chr7:72718277-74259899)x1	Pathogenic

SpliceAI

2830 predictions. Top by Δscore:

Variant	Effect	Δscore
7:73595648:T:TA	donor_gain	1.0000
7:73595649:C:A	donor_gain	1.0000
7:73595840:A:AC	donor_gain	1.0000
7:73595841:C:CC	donor_gain	1.0000
7:73595844:A:AC	donor_gain	1.0000
7:73595844:AATGG:A	donor_gain	1.0000
7:73595845:A:C	donor_gain	1.0000
7:73596148:CTCAC:C	donor_loss	1.0000
7:73596150:CACC:C	donor_loss	1.0000
7:73596152:C:CT	donor_loss	1.0000
7:73596275:C:CT	acceptor_gain	1.0000
7:73605766:AGG:A	acceptor_gain	1.0000
7:73605767:GG:G	acceptor_gain	1.0000
7:73605769:C:CC	acceptor_gain	1.0000
7:73605900:AGAC:A	donor_gain	1.0000
7:73605908:ACCAT:A	donor_gain	1.0000
7:73605909:CCATC:C	donor_gain	1.0000
7:73605912:T:TA	donor_gain	1.0000
7:73606112:C:CC	acceptor_gain	1.0000
7:73606112:CTAG:C	acceptor_loss	1.0000
7:73607330:CCCG:C	donor_gain	1.0000
7:73607417:CGGC:C	acceptor_gain	1.0000
7:73607591:T:TA	donor_gain	1.0000
7:73616069:A:AC	donor_gain	1.0000
7:73616070:C:CC	donor_gain	1.0000
7:73616070:CA:C	donor_gain	1.0000
7:73616173:TGCCA:T	acceptor_gain	1.0000
7:73616174:GCCA:G	acceptor_gain	1.0000
7:73616175:CCA:C	acceptor_gain	1.0000
7:73616175:CCAC:C	acceptor_gain	1.0000

AlphaMissense

5492 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:73595950:A:G	L693P	1.000
7:73594313:A:G	W801R	0.999
7:73594313:A:T	W801R	0.999
7:73595643:G:C	F768L	0.999
7:73595643:G:T	F768L	0.999
7:73595645:A:G	F768L	0.999
7:73595651:A:G	W766R	0.999
7:73595651:A:T	W766R	0.999
7:73596196:A:G	L672P	0.999
7:73596196:A:T	L672H	0.999
7:73596217:A:C	I665S	0.999
7:73596217:A:G	I665T	0.999
7:73596217:A:T	I665N	0.999
7:73596226:C:G	R662P	0.999
7:73596227:G:T	R662S	0.999
7:73596229:C:G	R661P	0.999
7:73607354:A:G	W184R	0.999
7:73607354:A:T	W184R	0.999
7:73616092:A:G	W127R	0.999
7:73616092:A:T	W127R	0.999
7:73616106:A:G	L122P	0.999
7:73616155:A:G	W106R	0.999
7:73616155:A:T	W106R	0.999
7:73594311:C:A	W801C	0.998
7:73594311:C:G	W801C	0.998
7:73594368:G:C	F782L	0.998
7:73594368:G:T	F782L	0.998
7:73594369:A:G	F782S	0.998
7:73594370:A:G	F782L	0.998
7:73594373:A:G	S781P	0.998

dbSNP variants (sampled 300 via entrez): RS1000024365 (7:73593257 C>A,T), RS1000159353 (7:73616897 G>C), RS1000211145 (7:73617156 C>T), RS1000225501 (7:73628030 C>T), RS1000372467 (7:73611823 A>T), RS1000496340 (7:73618349 G>A,T), RS1000600628 (7:73624631 C>G,T), RS1000670403 (7:73623420 C>T), RS1000695581 (7:73612758 C>G), RS1000809268 (7:73606776 T>C), RS1001057997 (7:73624770 G>A), RS1001092251 (7:73600898 C>A), RS1001135885 (7:73608165 C>T), RS1001141458 (7:73641812 T>C), RS1001188280 (7:73608488 G>A)

Disease associations

OMIM: gene MIM:605678 | disease phenotypes: MIM:194050

GenCC curated gene-disease

Mondo (2): myoepithelial tumor (MONDO:0002380), Williams syndrome (MONDO:0008678)

Orphanet (1): Williams syndrome (Orphanet:904)

HPO phenotypes

107 total (30 of 107 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000121	Nephrocalcinosis
HP:0000125	Pelvic kidney
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000403	Recurrent otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000539	Abnormality of refraction
HP:0000581	Blepharophimosis
HP:0000601	Hypotelorism
HP:0000629	Periorbital fullness
HP:0000635	Blue irides
HP:0000646	Amblyopia
HP:0000668	Hypodontia
HP:0000689	Dental malocclusion

GWAS associations

165 associations (top):

Study	Trait	p-value
GCST000137_3	Triglycerides	1.000000e-10
GCST000138_1	Triglycerides	7.000000e-22
GCST000139_5	Triglycerides	2.000000e-12
GCST000286_4	Triglycerides	3.000000e-15
GCST000289_8	Triglycerides	1.000000e-12
GCST000737_5	Hypertriglyceridemia	3.000000e-06
GCST000755_21	HDL cholesterol	1.000000e-09
GCST000758_21	Triglycerides	9.000000e-59
GCST000809_10	Triglycerides	2.000000e-12
GCST001230_5	Triglycerides	1.000000e-15
GCST001277_2	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-09
GCST001392_4	Lipid metabolism phenotypes	8.000000e-14
GCST001436_7	Metabolic syndrome	2.000000e-11
GCST001791_44	Urate levels	1.000000e-12
GCST001905_7	Hypertriglyceridemia	2.000000e-06
GCST002216_37	Triglycerides	9.000000e-99
GCST002223_45	HDL cholesterol	5.000000e-13
GCST002650_8	Coffee consumption (cups per day)	3.000000e-11
GCST002897_9	Triglycerides	1.000000e-40
GCST003217_3	Triglycerides	1.000000e-16
GCST003743_3	Hypertriglyceridemia	2.000000e-13
GCST003743_8	Hypertriglyceridemia	8.000000e-09
GCST004232_56	HDL cholesterol levels	5.000000e-13
GCST004237_37	Triglyceride levels	7.000000e-17
GCST004237_6	Triglyceride levels	2.000000e-110
GCST004238_8	Triglyceride levels	1.000000e-11
GCST004603_38	Platelet count	3.000000e-09
GCST004611_26	High light scatter reticulocyte count	8.000000e-16
GCST004612_35	High light scatter reticulocyte percentage of red cells	3.000000e-15
GCST004619_158	Reticulocyte fraction of red cells	3.000000e-16

EFO canonical traits (36, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004529	lipid measurement
EFO:0000195	metabolic syndrome
EFO:0004531	urate measurement
EFO:0004330	coffee consumption
EFO:0006782	cups of coffee per day measurement
EFO:0004309	platelet count
EFO:0007986	reticulocyte count
EFO:0004344	birth weight
EFO:0004761	uric acid measurement
EFO:0004574	total cholesterol measurement
EFO:0004619	factor VII measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004329	alcohol drinking
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0010093	bitter non-alcoholic beverage consumption measurement
EFO:0006781	coffee consumption measurement
EFO:0009282	sodium measurement
EFO:0008111	diet measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0010091	tea consumption measurement
EFO:0600007	fish oil supplement exposure measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585
D018980	Williams Syndrome	C10.597.606.360.970; C14.280.484.048.750.535.960; C16.131.260.970; C16.320.180.970

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, affects cotreatment, decreases expression	3
Cisplatin	affects expression, affects cotreatment, increases expression	3
Cyclosporine	decreases expression, decreases methylation	3
Aflatoxin B1	affects expression, decreases expression	3
perfluorooctane sulfonic acid	decreases expression	2
tebuconazole	increases expression, decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Dexamethasone	decreases expression, increases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Oleic Acid	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
dicrotophos	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	affects expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
enilconazole	decreases expression	1
periodate-oxidized adenosine	affects expression	1
cupric oxide	increases expression	1
propiconazole	affects cotreatment, increases expression	1
paxilline	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
fludioxonil	affects cotreatment, decreases expression	1
difenoconazole	affects cotreatment, decreases expression	1
GW 4064	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT04807517	PHASE4	COMPLETED	Buspirone Treatment of Anxiety in Williams Syndrome
NCT00876200	PHASE2	COMPLETED	Efficacy of Minoxidil in Children With Williams-Beuren Syndrome
NCT06087757	PHASE2	ACTIVE_NOT_RECRUITING	Clemastine Treatment in Individuals With Williams Syndrome
NCT06315699	PHASE2	COMPLETED	Clemastine Fumarate in the Treatment of Neurodevelopmental Delays in Williams Syndrome
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00013962	Not specified	COMPLETED	Vitamin D Metabolism and the Williams Syndrome
NCT01132885	Not specified	RECRUITING	Defining the Brain Phenotype of Children With Williams Syndrome
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01864304	Not specified	COMPLETED	Fat Distribution and Glucose Metabolism in Williams Syndrome
NCT02212314	Not specified	COMPLETED	Response Inhibition Training for Children With Williams Syndrome
NCT02692846	Not specified	COMPLETED	WS-SAVE Study (Williams Syndrome Skin and Vessel Elasticity Study)
NCT02706639	Not specified	COMPLETED	Williams Syndrome (WS) and Supravalvar Aortic Stenosis (SVAS) DNA and Tissue Bank
NCT02840448	Not specified	COMPLETED	Impact of Elastin Mediated Vascular Stiffness on End Organs
NCT03758651	Not specified	COMPLETED	Williams Syndrome Strength, Hormones, Activity & Adiposity, DNA Programming, Eating Study
NCT03827525	Not specified	UNKNOWN	Cognitive and Behavioral Therapy of Anxiety in Williams Syndrome
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04051086	Not specified	UNKNOWN	Quantification of Elastin Markers Synthesis in Williams-Beuren Syndrome and 7q11.23 Micro-duplication Syndrome
NCT04095585	Not specified	COMPLETED	Molecular Characterization of Patients Affected by Williams Syndrome and Autism.
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04610424	Not specified	UNKNOWN	Cooperative Parent Mediated Therapy in Children With Fragile X Syndrome and Williams Syndrome
NCT05430763	Not specified	WITHDRAWN	Motor Deficits and Signal Conduction in Individuals With Williams Syndrome
NCT06740162	Not specified	RECRUITING	Physical Activity and Community EmPOWERment Project
NCT06930417	Not specified	RECRUITING	Characterization and Natural History of Williams Syndrome and Other Chromosome 7q11.23 Variants
NCT07285720	Not specified	RECRUITING	Phonological Constraints on Language Development in Individuals With Williams Syndrome
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders
NCT07509879	Not specified	NOT_YET_RECRUITING	Research on the Molecular Mechanism of Cognitive Differences Between Williams Syndrome and Autism Spectrum Disorder
NCT07537374	Not specified	NOT_YET_RECRUITING	A Case-Control Observational Study of Peripheral Blood-Derived iPSC Models to Investigate Oligodendrocyte Lineage Development in Children With Williams Syndrome and Healthy Controls