SIM1

Summary

SIM1 (SIM bHLH transcription factor 1, HGNC:10882) is a protein-coding gene on chromosome 6q16.3, encoding Single-minded homolog 1 (P81133). Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.

SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. SIM1 transcript was detected only in fetal kidney out of various adult and fetal tissues tested. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis,it was proposed that the human SIM gene is a candidate for involvement in certain dysmorphic features (particularly the facial and skull characteristics), abnormalities of brain development, and/or cognitive disability of Down syndrome.

Source: NCBI Gene 6492 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obesity due to SIM1 deficiency (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 455 total — 4 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 98
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005068

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10882
Approved symbol	SIM1
Name	SIM bHLH transcription factor 1
Location	6q16.3
Locus type	gene with protein product
Status	Approved
Aliases	bHLHe14
Ensembl gene	ENSG00000112246
Ensembl biotype	protein_coding
OMIM	603128
Entrez	6492

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000262901, ENST00000369208, ENST00000505753, ENST00000511871, ENST00000900753

RefSeq mRNA: 2 — MANE Select: NM_005068 NM_001374769, NM_005068

CCDS: CCDS5045

Canonical transcript exons

ENST00000369208 — 12 exons

Exon	Start	End
ENSE00000760968	100393487	100393889
ENSE00000760969	100420790	100420958
ENSE00000760971	100448146	100448252
ENSE00000760973	100449363	100449448
ENSE00000760976	100453762	100453844
ENSE00000840240	100449591	100449699
ENSE00000840241	100450267	100450356
ENSE00001449122	100463294	100463935
ENSE00001449139	100385009	100391091
ENSE00002083674	100464614	100464921
ENSE00002498141	100448479	100448678
ENSE00002527488	100447268	100447415

Expression profiles

Bgee: expression breadth broad, 76 present calls, max score 94.05.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6483 / max 63.1943, expressed in 217 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74827	0.3336	172
74826	0.2962	118
74825	0.0185	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	94.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.30	gold quality
biceps brachii	UBERON:0001507	89.61	gold quality
penis	UBERON:0000989	85.99	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.11	gold quality
corpus epididymis	UBERON:0004359	83.74	gold quality
caput epididymis	UBERON:0004358	82.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.14	gold quality
vastus lateralis	UBERON:0001379	80.04	silver quality
islet of Langerhans	UBERON:0000006	79.22	gold quality
quadriceps femoris	UBERON:0001377	77.99	silver quality
metanephros cortex	UBERON:0010533	77.96	gold quality
kidney	UBERON:0002113	77.52	gold quality
skeletal muscle tissue	UBERON:0001134	77.11	gold quality
nephron tubule	UBERON:0001231	76.24	gold quality
adult mammalian kidney	UBERON:0000082	76.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.29	gold quality
epithelial cell of pancreas	CL:0000083	74.20	silver quality
metanephros	UBERON:0000081	73.08	gold quality
deltoid	UBERON:0001476	73.08	silver quality
kidney epithelium	UBERON:0004819	72.63	gold quality
cortex of kidney	UBERON:0001225	71.95	gold quality
seminal vesicle	UBERON:0000998	71.69	gold quality
muscle tissue	UBERON:0002385	71.00	gold quality
tibialis anterior	UBERON:0001385	70.31	silver quality
pancreas	UBERON:0001264	69.16	gold quality
metanephric glomerulus	UBERON:0004736	68.69	silver quality
renal glomerulus	UBERON:0000074	68.59	silver quality
cauda epididymis	UBERON:0004360	68.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.34

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
AHR	Repression
ARNT2
EPO
OXT	Unknown

Upstream regulators (CollecTRI, top): AHR, ARNT2, ARNT, DNMT3A, HIF1A, WT1

miRNA regulators (miRDB)

112 targeting SIM1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3919	99.87	69.45	2489

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 25)

• Haploinsufficiency of the SIM1 gene might be responsible for the severe obesity observed in a child with a Prader-Willi-like phenotype. (PMID:12161602)
• SIM1 and SIM2 have a novel nuclear localization signal (PMID:14697214)
• SIM1 transgene completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice (PMID:16709610)
• Common variation in SIM1 is associated with body mass index on a population level in Pima Indians where the risk allele is the major allele. (PMID:19401419)
• Our study excludes a major contribution of SIM1 common variants in exons, 5’ and 3’ UTR regions in polygenic obesity susceptibility in French Europeans. (PMID:20075856)
• Hyperphagic obesity in single-minded homolog 1 (Sim1)-deficient mice may be attributable to transgenic changes in the leptin-melanocortin-oxytocin pathway. (PMID:20220015)
• TagSNP analysis of SIM1 revealed two SNPs in the 3’ region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity- and sex-specific manners… (PMID:21512513)
• Data indicate that median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >/=30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. (PMID:22930747)
• A link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features. (PMID:23778136)
• Phenotypic similarities between patients with SIM1 deficiency and MC4R deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling. (PMID:23778139)
• Hence, we suggest that detailed endocrine evaluation and longitudinal endocrine follow up be performed in individuals with proximal interstitial 6q deletion involving SIM1 (PMID:24038875)
• functional in vitro analysis of SIM1 variants may help in distinguishing benign variants of no pathogenic significance from variants which contribute to the obesity phenotype. (PMID:24097297)
• two brain enhancers in the SIM1 locus are characterized with a set of obesity-specific SNPs within one of them, which may predispose individuals to obesity. (PMID:24203700)
• Study found a statistically significant association between the SIM1 SNP rs3734354 (Pro352Thr) and scores for language impairment (p = .0004), but due to low statistical power this should be interpreted cautiously (PMID:24635660)
• Data suggest selected SIM1 variants exhibit poor dimerization with ARNT2 (aryl-hydrocarbon receptor nuclear translocator 2) and anomalous intracellular localization; data were used to predict spot in SIM1/SIM2 (residues 290-326) critical in function. (PMID:24814368)
• Severe loss-of-function SIM1 mutations can be associated with a spectrum of developmental delay phenotypes and obesity. (PMID:25234154)
• Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the Prader-Willi-like phenotype (PMID:25351778)
• Aberrant DNA methylation of the DLX4 and SIM1 genes may be a novel progression marker for uterine cervical low-grade squamous intraepithelial lesions. (PMID:25614457)
• no gene harboring deletions were identified in the SIM1 and MRAP2 regions in the Prader Willi like (PWL) cohort; further functional analysis of p.P352S found in SIM1 and p.A40S found in MRAP2 is useful; this would provide further support for possible role of SIM1 and MRAP2 in the pathogenesis of the PWL phenotype in a limited number of patients (PMID:26795956)
• identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods (PMID:28472148)
• Single nucleotide polymorphism rs3734354 in SIM1 gene is associated with severe early-onset obesity. (PMID:28593922)
• SIM1 was highly methylated in the majority of the cervical cancer tissues. Hypermethylation of SIM1 led to a pronounced reduction in SIM1 expression in cervical cancer tissues compared with normal cervix. The degree of SIM1 methylation was significantly associated with the severity of the disease. (PMID:29063719)
• SIM1 is part of the leptin-melanocortin system. (PMID:30297428)
• Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain. (PMID:32932609)
• STIM1/SOX2 proteins are co-expressed in the tumor and microenvironmental stromal cells of pancreatic ductal adenocarcinoma and ampullary carcinoma. (PMID:38532463)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sim1a	ENSDARG00000023316
danio_rerio		ENSDARG00000039935
mus_musculus	Sim1	ENSMUSG00000019913
rattus_norvegicus	Sim1	ENSRNOG00000037600
drosophila_melanogaster	trh	FBGN0262139
caenorhabditis_elegans		WBGENE00001851

Paralogs (7): HIF1A (ENSG00000100644), EPAS1 (ENSG00000116016), HIF3A (ENSG00000124440), NPAS1 (ENSG00000130751), NPAS3 (ENSG00000151322), SIM2 (ENSG00000159263), NPAS4 (ENSG00000174576)

Protein

Protein identifiers

Single-minded homolog 1 — P81133 (reviewed: P81133)

Alternative names: Class E basic helix-loop-helix protein 14

All UniProt accessions (1): P81133

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimer; forms a heterodimer with ARNT, ARNT2.

Subcellular location. Nucleus.

RefSeq proteins (2): NP_001361698, NP_005059* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001610	PAC	Repeat
IPR010578	SIM_C	Domain
IPR011598	bHLH_dom	Domain
IPR013655	PAS_fold_3	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00989, PF06621, PF08447, PF23171

UniProt features (17 total): domain 5, compositionally biased region 3, sequence variant 3, sequence conflict 2, region of interest 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P81133-F1	60.70	0.31

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 313 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, TAL1ALPHAE47_01, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, FREAC3_01, IRF1_Q6, HFH8_01, TCF11_01, MODULE_123, TATA_C, AACTTT_UNKNOWN, AFFAR_YY1_TARGETS_UP, E12_Q6, GOBP_MESONEPHROS_DEVELOPMENT, TAL1BETAE47_01

GO Biological Process (6): ureteric bud development (GO:0001657), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355), system development (GO:0048731)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
mesonephric tubule development	1
transcription by RNA polymerase II	1
system development	1
cellular developmental process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
multicellular organism development	1
anatomical structure development	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription regulator activity	1
protein dimerization activity	1
binding	1
protein binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1046 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIM1	ARNT2	Q9HBZ2	928
SIM1	OTP	Q5XKR4	859
SIM1	MC4R	P32245	839
SIM1	MCHR2	Q969V1	819
SIM1	OXT	P01178	788
SIM1	POMC	P01189	728
SIM1	POU3F2	P20265	708
SIM1	ARNT	P27540	679
SIM1	TRH	P20396	674
SIM1	AGRP	O00253	671
SIM1	LEP	P41159	658
SIM1	SLC32A1	Q9H598	622
SIM1	MRAP2	Q96G30	564
SIM1	PCSK1	P29120	548
SIM1	DBX1	A6NMT0	533

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ARNT2	SIM1	psi-mi:“MI:0915”(physical association)	0.560
SIM1	ARNT2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): ARNT2 (FRET), SIM1 (FRET), SIM1 (Affinity Capture-Western), ARNT (Reconstituted Complex), ARNT2 (Two-hybrid), SIM1 (Two-hybrid), SIM1 (Reconstituted Complex), HSP90AA1 (Reconstituted Complex), SIM1 (Affinity Capture-Western), SIM1 (Affinity Capture-MS), SIM1 (Affinity Capture-MS), SIM1 (Co-localization), SIM1 (Proximity Label-MS), SIM1 (Proximity Label-MS), SIM1 (Proximity Label-MS)

ESM2 similar proteins: A1YFY6, A2T6X9, A6H7I8, B2RUJ5, F1M5F3, F1N2W9, O35430, O35431, O95487, O95628, O95644, P0C6S7, P14316, P17863, P22681, P22682, P23798, P23906, P35227, P81133, P98084, Q02410, Q0IHY4, Q13469, Q14190, Q14432, Q1L994, Q3UR85, Q52L14, Q5CD77, Q5RD33, Q60591, Q61045, Q61079, Q66JB6, Q69ZT9, Q6NRE7, Q6QB00, Q8BIZ1, Q8BT14

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, E7FFX1, O02747, O44712, O57539, O61734, P30561, P35869, P41738, P70365

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SIM1	“down-regulates activity”	ARNT	binding
SIM1	“up-regulates activity”	ARNT	binding
SIM1	“down-regulates activity”	AHR-ARNT	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	7
Uncertain significance	293
Likely benign	106
Benign	29

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1699502	NM_005068.3(SIM1):c.616del (p.Gln206fs)	Pathogenic
2580107	NM_005068.3(SIM1):c.1302C>A (p.Cys434Ter)	Pathogenic
2844233	NM_005068.3(SIM1):c.641del (p.Gly214fs)	Pathogenic
4532010	NM_005068.3(SIM1):c.309del (p.Met102_Tyr103insTer)	Pathogenic
1803836	NM_005068.3(SIM1):c.793_794del (p.Leu265fs)	Likely pathogenic
3347931	NM_005068.3(SIM1):c.106C>T (p.Gln36Ter)	Likely pathogenic
3349174	NM_005068.3(SIM1):c.1431C>A (p.Tyr477Ter)	Likely pathogenic
3354911	NM_005068.3(SIM1):c.999-2A>G	Likely pathogenic
373292	NM_005068.3(SIM1):c.1298C>A (p.Ser433Ter)	Likely pathogenic
421271	NM_005068.3(SIM1):c.2123A>G (p.Lys708Arg)	Likely pathogenic
987866	NM_005068.3(SIM1):c.1438G>T (p.Gly480Ter)	Likely pathogenic

SpliceAI

2265 predictions. Top by Δscore:

Variant	Effect	Δscore
6:100393897:CGAG:C	acceptor_gain	1.0000
6:100420785:CTTA:C	donor_loss	1.0000
6:100420786:TTA:T	donor_loss	1.0000
6:100420787:TACC:T	donor_loss	1.0000
6:100420955:GTCT:G	acceptor_gain	1.0000
6:100420957:CT:C	acceptor_gain	1.0000
6:100420959:C:CC	acceptor_gain	1.0000
6:100447416:C:CC	acceptor_gain	1.0000
6:100448144:A:AC	donor_gain	1.0000
6:100448145:C:CT	donor_gain	1.0000
6:100448145:CG:C	donor_gain	1.0000
6:100448475:CCAC:C	donor_loss	1.0000
6:100448476:CA:C	donor_loss	1.0000
6:100448477:ACC:A	donor_loss	1.0000
6:100448478:C:CA	donor_loss	1.0000
6:100448674:ATGAC:A	acceptor_gain	1.0000
6:100448675:TGAC:T	acceptor_gain	1.0000
6:100448676:GAC:G	acceptor_gain	1.0000
6:100448677:AC:A	acceptor_gain	1.0000
6:100448678:CC:C	acceptor_gain	1.0000
6:100448679:C:CC	acceptor_gain	1.0000
6:100448685:C:CT	acceptor_gain	1.0000
6:100448686:A:T	acceptor_gain	1.0000
6:100449359:GCAC:G	donor_loss	1.0000
6:100449360:CA:C	donor_loss	1.0000
6:100449361:ACCT:A	donor_loss	1.0000
6:100449362:C:CG	donor_loss	1.0000
6:100449444:ATACT:A	acceptor_gain	1.0000
6:100449445:TACT:T	acceptor_gain	1.0000
6:100449447:CT:C	acceptor_gain	1.0000

AlphaMissense

5033 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:100447271:A:G	L332P	1.000
6:100447274:A:T	V331D	1.000
6:100447279:G:C	N329K	1.000
6:100447279:G:T	N329K	1.000
6:100447283:A:T	V328D	1.000
6:100447285:G:C	S327R	1.000
6:100447285:G:T	S327R	1.000
6:100447287:T:G	S327R	1.000
6:100447289:A:T	V326D	1.000
6:100447292:A:T	I325N	1.000
6:100447294:A:C	C324W	1.000
6:100447295:C:T	C324Y	1.000
6:100447296:A:G	C324R	1.000
6:100447303:C:A	R321S	1.000
6:100447303:C:G	R321S	1.000
6:100447304:C:A	R321M	1.000
6:100447304:C:G	R321T	1.000
6:100447310:G:A	S319F	1.000
6:100447314:G:T	R318S	1.000
6:100447318:G:C	N316K	1.000
6:100447318:G:T	N316K	1.000
6:100447339:G:C	S309R	1.000
6:100447339:G:T	S309R	1.000
6:100447340:C:A	S309I	1.000
6:100447341:T:G	S309R	1.000
6:100447343:T:G	Q308P	1.000
6:100447348:C:A	W306C	1.000
6:100447348:C:G	W306C	1.000
6:100447350:A:G	W306R	1.000
6:100447350:A:T	W306R	1.000

dbSNP variants (sampled 300 via entrez): RS1000037524 (6:100389324 G>A,T), RS1000064070 (6:100441084 T>C), RS1000071908 (6:100466016 C>T), RS1000111590 (6:100398501 G>T), RS1000142678 (6:100398202 T>C), RS1000174752 (6:100425447 G>A), RS1000177250 (6:100421437 A>G), RS1000237767 (6:100434693 T>A), RS1000279181 (6:100392264 C>A,T), RS1000426733 (6:100440776 A>G), RS1000434199 (6:100456892 A>C,G), RS1000540113 (6:100416641 T>C), RS1000544986 (6:100464477 G>A,T), RS1000565274 (6:100422623 G>A,T), RS1000609260 (6:100422703 A>G)

Disease associations

OMIM: gene MIM:603128 | disease phenotypes: MIM:157900

GenCC curated gene-disease

Disease	Classification	Inheritance
obesity due to SIM1 deficiency	Definitive	Autosomal dominant
complex neurodevelopmental disorder	Strong	Autosomal dominant
inherited obesity	Strong	Autosomal dominant

Mondo (8): obesity disorder (MONDO:0011122), obesity due to SIM1 deficiency (MONDO:0018244), Mobius syndrome (MONDO:0008006), monogenic diabetes (MONDO:0015967), brachydactyly (MONDO:0021004), microcephaly (MONDO:0001149), complex neurodevelopmental disorder (MONDO:0100038), inherited obesity (MONDO:0019182)

Orphanet (5): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Obesity due to SIM1 deficiency (Orphanet:369873), Rare genetic diabetes mellitus (Orphanet:183625), Moebius syndrome (Orphanet:570), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

98 total (30 of 98 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000135	Hypogonadism
HP:0000217	Xerostomia
HP:0000219	Thin upper lip vermilion
HP:0000256	Macrocephaly
HP:0000278	Retrognathia
HP:0000293	Full cheeks
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000446	Narrow nasal bridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000765	Abnormal thorax morphology
HP:0000786	Primary amenorrhea
HP:0000789	Infertility

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST002541_25	Menarche (age at onset)	3.000000e-16
GCST002541_51	Menarche (age at onset)	9.000000e-14
GCST002541_52	Menarche (age at onset)	8.000000e-12
GCST002541_53	Menarche (age at onset)	3.000000e-08
GCST004110_16	Gait speed in old age	8.000000e-06
GCST005232_142	Neuroticism	2.000000e-08
GCST005959_26	Waist-to-hip ratio adjusted for BMI x sex interaction	6.000000e-06
GCST005984_47	Glomerular filtration rate	2.000000e-09
GCST005985_25	Creatinine levels	5.000000e-09
GCST006041_19	Major depressive disorder	6.000000e-08
GCST006940_53	Neurociticism	4.000000e-08
GCST006941_23	Irritable mood	5.000000e-09
GCST007118_1	Erectile dysfunction	2.000000e-37
GCST007743_16	Iris color (L* coordinate)	4.000000e-06
GCST008058_235	Estimated glomerular filtration rate	8.000000e-09
GCST008078_120	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-09
GCST008078_25	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-11
GCST008079_127	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-09
GCST008079_59	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-10
GCST008086_46	LDL cholesterol levels in current drinkers	6.000000e-09
GCST008086_75	LDL cholesterol levels in current drinkers	5.000000e-08
GCST010989_109	Body size at age 10	3.000000e-26
GCST012114_8	Sociability score	1.000000e-08
GCST012114_9	Sociability score	1.000000e-08
GCST012490_129	Femur bone mineral density x serum urate levels interaction	2.000000e-08
GCST012490_409	Femur bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007660	neuroticism measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008343	sex interaction measurement
EFO:0009594	irritability measurement
EFO:0009764	eye colour measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0009819	comparative body size at age 10, self-reported
EFO:0009592	social interaction measurement
EFO:0004531	urate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D059327	Brachydactyly	C05.660.585.262; C16.131.621.585.262
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
PF-06840003	decreases reaction, increases expression	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
arsenite	increases methylation	1
sodium arsenite	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Coal	increases abundance, increases expression	1
Estradiol	decreases expression	1
Folic Acid	decreases expression, affects cotreatment	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Methotrexate	decreases expression, affects cotreatment	1
Nickel	decreases expression	1
Smoke	increases abundance, increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	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_A6D0	SEES3-1V human SIM1, clone1	Embryonic stem cell	Male
CVCL_A6D1	SEES3-1V human SIM1, clone2	Embryonic stem cell	Male
CVCL_A6D2	SEES3-1V human SIM1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	PHASE4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients