• Gene id: 3640

Gene Summary

• Gene Symbol: INSL3   Gene   UCSC   Ensembl
• Aliases: RLF, RLNL, ley-I-L
• Gene name: insulin like 3
• Alternate names: insulin-like 3, insulin-like 3 (Leydig cell), leydig insulin -like hormone, leydig insulin-like peptide, prepro-INSL3, relaxin-like factor b,
• Gene location: 19p13.11 (17821573: 17816512)     Exons: 3     NC_000019.10
• Gene summary(Entrez): This gene encodes a member of the insulin-like hormone superfamily. The encoded protein is mainly produced in gonadal tissues. Studies of the mouse counterpart suggest that this gene may be involved in the development of urogenital tract and female fertil
• OMIM: 146738

SNPs

rs121912556

Strand:    Allele origin:   Allele change:   Mutation type: snv

NC_000019.10   g.17816945C>T
NC_000019.9   g.17927754C>T
NG_012092.1   g.9567G>A
NM_005543.4   c.305G>A
NM_005543.3   c.305G>A
NM_001265587.2   c.400G>A
NM_001265587.1   c.400G>A
NP_005534.2   p.Arg102His
NP_001252516.1   p.Ala134Thr|SEQ=[C/T]|GENE=INSL3

rs10421916

Strand:    Allele origin:   Allele change:   Mutation type: snv

NC_000019.10   g.17818178A>G
NC_000019.10   g.17818178A>T
NC_000019.9   g.17928987A>G
NC_000019.9   g.17928987A>T
NG_012092.1   g.8334T>C
NG_012092.1   g.8334T>A|SEQ=[A/G/T]|GENE=INSL3

Protein Summary

• Protein general information: P51460  
  • Name: Insulin like 3 (Leydig insulin like peptide) (Ley I L) (Relaxin like factor) [Cleaved into: Insulin like 3 B chain; Insulin like 3 A chain]
  • Length: 131  
  • Mass: 14,502
• Sequence:

  MDPRLPAWALVLLGPALVFALGPAPTPEMREKLCGHHFVRALVRVCGGPRWSTEARRPATGGDRELLQWLERRHL
  LHGLVADSNLTLGPGLQPLPQTSHHHRHHRAAATNPARYCCLSGCTQQDLLTLCPY

• Structural information:
  • Interpro: IPR016179  IPR036438  IPR022353  
  • Prosite: PS00262
  • PDB: 2H8B 2K6T 2K6U
  • PDBsum: 2H8B 2K6T 2K6U
  • STRING: ENSP00000321724
• Other Databases: GeneCards:  INSL3  Malacards:  INSL3

Gene ontology

GO accession	Term name	Evidence code	Go category
GO:0001556	oocyte maturation	IEA	biological process
GO:0001664	G-protein coupled receptor binding	IEA	molecular function
GO:0002020	protease binding	IPI	molecular function
GO:0005102	receptor binding	TAS	molecular function
GO:0005158	insulin receptor binding	TAS	molecular function
GO:0005179	hormone activity	IEA	molecular function
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005615	extracellular space	IEA	cellular component
GO:0007193	adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway	IEA	biological process
GO:0007267	cell-cell signaling	TAS	biological process
GO:0007283	spermatogenesis	TAS	biological process
GO:0008284	positive regulation of cell proliferation	IEA	biological process
GO:0008285	negative regulation of cell proliferation	IEA	biological process
GO:0008584	male gonad development	IEA	biological process
GO:0010634	positive regulation of epithelial cell migration	IDA	biological process
GO:0030819	positive regulation of cAMP biosynthetic process	IEA	biological process
GO:0043066	negative regulation of apoptotic process	IEA	biological process
GO:0048471	perinuclear region of cytoplasm	IEA	cellular component
GO:0090303	positive regulation of wound healing	IDA	biological process
GO:0001556	oocyte maturation	IEA	biological process
GO:0001664	G-protein coupled receptor binding	IEA	molecular function
GO:0002020	protease binding	IPI	molecular function
GO:0005102	receptor binding	TAS	molecular function
GO:0005158	insulin receptor binding	TAS	molecular function
GO:0005179	hormone activity	IEA	molecular function
GO:0005179	hormone activity	IEA	molecular function
GO:0005576	extracellular region	IEA	cellular component
GO:0005576	extracellular region	IEA	cellular component
GO:0005576	extracellular region	IEA	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005615	extracellular space	IEA	cellular component
GO:0007193	adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway	IEA	biological process
GO:0007267	cell-cell signaling	TAS	biological process
GO:0007283	spermatogenesis	TAS	biological process
GO:0008284	positive regulation of cell proliferation	IEA	biological process
GO:0008285	negative regulation of cell proliferation	IEA	biological process
GO:0008584	male gonad development	IEA	biological process
GO:0010634	positive regulation of epithelial cell migration	IDA	biological process
GO:0030819	positive regulation of cAMP biosynthetic process	IEA	biological process
GO:0043066	negative regulation of apoptotic process	IEA	biological process
GO:0048471	perinuclear region of cytoplasm	IEA	cellular component
GO:0090303	positive regulation of wound healing	IDA	biological process
GO:0002020	protease binding	IPI	molecular function
GO:0005102	receptor binding	TAS	molecular function
GO:0005158	insulin receptor binding	TAS	molecular function
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0005576	extracellular region	TAS	cellular component
GO:0007267	cell-cell signaling	TAS	biological process
GO:0007283	spermatogenesis	TAS	biological process
GO:0010634	positive regulation of epithelial cell migration	IDA	biological process
GO:0090303	positive regulation of wound healing	IDA	biological process

KEGG pathways

Pathway id	Pathway name
hsa04080	Neuroactive ligand-receptor interaction
hsa04926	Relaxin signaling pathway

Diseases

Associated diseases	References
Cancer	GAD: 16687567
Cancer (meningeal)	GAD: 20406964
Noonan syndrome	KEGG: H00523
Low ovarian reserve	INFBASE: 24014601
Functional ovarian hyperandrogenism	INFBASE: 21586896
Anorchia	INFBASE: 15579790
Klinefelter syndrome	INFBASE: 15755855
Hypogonadotropic hypogonadism	INFBASE: 15755855
Congenital hypogonadotropic hypogonadism (CHH)	INFBASE: 24243640
Kallmann syndrome (KS)	INFBASE: 24243640
Polycystic ovary syndrome (PCOS)	INFBASE: 23928669
Undermasculinised genitalia and intra-abdominal or inguinal gonads	INFBASE: 11182749
Ovarian dysfunction	INFBASE: 26579638
Azoospermia	MIK: 26840636
Congenital hypogonadotropic hypogonadism (CHH)	MIK: 24243640
Oligoasthenoteratozoospermia	MIK: 17559848
Hypogonadotropic hypogonadism	MIK: 15755855
Cryptorchidism	MIK: 24243640
Leydig cell dysfunction	MIK: 16926256
Male factor infertility	MIK: 18611973
Maldescended testes	MIK: 11182749
Bilateral cryptorchidism	MIK: 17559848
Azoospermia	MIK: 12970298
Testicular disorders	MIK: 15755855
Testicular dysgenesis syndrome (TDS)	MIK: 16687567
Testicular functions	MIK: 15353080
Nonsyndromic cryptorchidism	MIK: 26209787
Testicular maldescent	MIK: 11182749
Testicular maldescent	MIK: 25728210
Testicular pathologies	MIK: 24908673
Retractile testes	MIK: 15353080
Hypospermatogenesis	MIK: 15579743
Non obstructive azoospermia	MIK: 17559848
Male factor infertility	MIK: 15533513
Cryptorchidism	MIK: 10729310
Hypospadias	MIK: 17437853
Cryptorchidism	MIK: 11095425
Short stature	INFBASE: 16926256
Azoospermia	MIK: 26840636
Cryptorchidism	MIK: 26840636
Bilateral cryptorchidism	MIK: 10319319
Congenital hypogonadotropic hypogonadism	MIK: 24243640
Kallmann syndrome	MIK: 24243640
Testicular disorders	MIK: 15353080
Important for testicular descent	MIK: 23100620
Klinefelter syndrome	MIK: 24908673
Maldescended testes	MIK: 16687567
Testicular dysgenesis syndrome	MIK: 16687567
Nonobstructive male infertility	MIK: 17559848
Nonsyndromic cryptorchidism	MIK: 26209787
Testicular maldescent	MIK: 25728210

PubMed references

PMID	Condition	Mutation	Ethnicity	Population details	Infertility_type	Associated_genes
24243640	Infertility			281 CHH/KS patients (91 untreated, 96 receiving T, and 94 receiving combined gonadotropin therapy [human chorionic gonadotropin, hCG, and FSH]), 72 age-matched healthy men	Male infertility
21307139	Infertility	XXY genotype		50 controls, 68 patients	Male infertility
19416190	Infertility	Two mutations in the INSL3 gene		300 noncryptorchid subjects, 600 newborns with cryptorchidism (396 unilateral and 204 bilateral)	Male infertility	RXFP2
19017913	Infertility	R102C, T86M	Italian	300 noncryptorchid male children, 600 male infants with cryptorchidism	Male infertility	RXFP2 AR
18611973	Infertility			93 (45 males and 48 females)	Male infertility	Testosterone
17666478	Infertility		Danish, Finnis h	267 boys ( 151 controld, 54 Transiently cryptorchid, 62 Persistently cryptorchid), 26 prepubertal boys (aged 4.1–10.1 yr) , 13 healthy Danish prepubertal girls (aged 3.7– 8.7 yr)	Male infertility
17559848	Infertility			205 infertile men ( 102 azoospermia, 143 oligo-asthenoteratozoospermia )	Male infertility
17437853	Infertility	C-19G, V18M and R105H		270 controls (127 fertile, and 143 fertile noncryptorchid males), 184 patients (52 with unilateral cryptorchidism, 37 with bilateral cryptorchidism, 19 with cryptorchidism and hypospadias, 1 with bilateral cryptorchidism and micropenis, 75 with isolated h	Male infertility	LGR8
16926256	Infertility	47,XXY		30 healthy boys with ISS, 14 boys with Klinefelter syndrome (KS)	Male infertility	LH
15956751	Infertility				Male infertility
15755855	Infertility	47,XXY	Danish	135 controls, 85 patients ( 23 infertile men, 21 anorchid men, 21 Klinefelter syndrome, 11 with hypogonadotropic hypogonadism and T substitution, 5 with hypogonadotropic hypogonadism and human chorionic gonadotropin (hCG) treatment)	Male infertility	LH Testosterone
15579790	Infertility			14 patients with anorchia	Male infertility	LGR8 SRY
15579743	Infertility	47, XXY		50 normal (40 male, 10 female), 52 patients (5 untreated orchidectomized men, 9 Klinefelter’s syndrome and azoospermia, 32 severely infertile men, 6 HH)	Male infertility	LH FSH Testosterone
155335	Infertility	2 silent substitutions and one missense (A60T) substitution in exon 1		13 patients with cryptorchidism	Male infertility	Great/Lgr8
15353080	Infertility			100 controls, 135 ex-cryptorchid patients	Male infertility	LGR8/GREAT
12970298	Infertility	INSL3 (L9L (27G->A), A60T (178G>A), L42L (126G>A), 278C>T (P93L), 304C>T(R102C), and 305G>A (R102H)), LGR8 (T222P, INV2(+15)C >T, Exon 3 (261G> A A87A), INV4(+17)T>A), Exon 12 957G> A E319E, Exon 12 993A-> G L331L, INV12( -2)A9> A13, Exon 17 1810A> G I604		80 controls, 87 ex-cryptorchid patients	Male infertility	LGR8/GREAT
12601553	Infertility	In exon 2, a heterozygous C/G substitution at nucleotide 2560 -> N86K , G to A substitution at nucleotide 1167 encoding alanine, G to A substitution at nucleotide 1266 encoding leucine, a G-to-A substitution at nucleotide 1318 which turned alanine into t	Mexican mestiz o ethni c origi n	50 controls, 150 patients with idiopathic unilateral (left,n 48; right, n 57) or bilateral (n 45) cryptorchidism	Male infertility
11992081	Infertility	2 silent mutations, 1 missense mutations		118 patients with cryptorchidism, 48 normal controls	Male infertility
11383919	Infertility	single base substitutions from G to A at position 27, 96, 126 and 178 in exon1, 178G-->A substitution ->(A60T)		65 ex-cryptorchid patients, controls	Male infertility
11380919	Infertility	G to A transition at position 178 -> A60T	Japanes e	70 controls, 5 patients with sporadic bilateral cryptorchidism	Male infertility
11182749	Infertility	A-1G, V19L, P25S, A36T, R78H		126 controls (15 normal males, 29 males with undermasculinised genitalia and scrotal gonads, 82 females), 85 patients (28 with isolated testicular maldescent, 24 patients with undermasculinised genitalia and intra-abdominal, 33 patients with inguinal gon	Male infertility
11095425	Infertility	G->A at nucleotide position 1266 in exon 1, G->A at nucleotide position 1318 in exon1 -> A36T, a C->T mutation at nucleotide 2450 in exon2 -> R49X, C->T change at nucleotide 2511 in exon 2 -> P69L, C->T nucleotide change at nucleotide 1259 located in the		36 male controls, 145 males ex-cryptorchidism patients	Male infertility
10759163	Infertility	G178A		89 controls, 30 patients ( 7 familial cryptorchidism, 23 sporadic cryptorchidism)	Male infertility
10729310	Infertility		Europea n	31 patients with idiopathic bilateral or unilateral cryptorchidism, 9 controls	Male infertility
15533513	Infertility	A missense (A60T) substitution in exon 1 of INSL3 and two silent substitutions in exon 12 and one missense (I604V) substitution in exon 17 of GREAT		13 familial cryptorchidism	Male infertility	LGR8
24908673	Klinefelter syndrome, Testicular pathologies			91 (33 fetal and prepubertal human specimens and in 58 adult testis samples from patients with testicular germ cell tumours,)	Male infertility	DLK1 INSL3 COUP-TFII cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1) and smooth muscle actin (SMA)
15353080	Cryptorchidism, Testicular functions			235 (135 ex-cryptorchid patients, 100 controls)	Male infertility	INSL3 LGR8/GREAT
24826892	Idiopathic cryptorchidism			180 (52 cryptorchid (48 unilateral, 4 bilateral; 26 transient, 26 persistent), 128 controls)	Male infertility
26840636	Azoospermia, Cryptorchidism	INSL3 G178A polymorphism		146 (97 azoospermic patients with a history of bilateral cryptorchidism (patient group) versus, 49 males with obstructive azoospermia (control group))	Male infertility
26209787	Nonsyndromic cryptorchidism		Europea n	3562 (844 boys with nonsyndromic cryptorchidism, 2718 control subjects without syndromes or genital anomalies)	Male infertility	INSL3 RXFP2
25728210	Testicular maldescent	INSL3 gene polymorphisms (27G>A, 126G>A, 178G>A)	Greek	220 (170 unrelated children with testicular maldescent, 50 volunteers with normal external genitalia as controls)	Male infertility
24826892	Idiopathic cryptorchidism			180 (52 cryptorchid (48 unilateral, 4 bilateral; 26 transient, 26 persistent), 128 controls)	Male infertility, Female infertility
20569797	Cryptorchidism				Male infertility
19017913	Cryptorchidism			900 (600 male infants with cryptorchidism, 300 noncryptorchid male children as controls)	Male infertility
17666478	Cryptorchidism			314 (151 controls, 54 transiently cryptorchid, 62 persistently cryptorchid subjects, 8 infant girls, 26 boys, 13 girls)	Male infertility
17559848	Nonobstructive male infertility, bilateral cryptorchidism	INSL3 G178A polymorphism			Male infertility
17437853	Cryptorchidism	INSL3 variants (C-19G, V18M and R105H)		454 (184 patients (52 presented with unilateral cryptorchidism, 37 presented with bilateral cryptorchidism, 19 presented with cryptorchidism and hypospadias, 1 presented with bilateral cryptorchidism and micropenis, and 75 presented with isolated hypospad	Male infertility	INSL3 LGR8 receptor
17028442	Cryptorchidism	Ala60Thr polymorphism in INSL3	Japanes e	122 (62 patients with cryptorchidism, 60 fertile controls)	Male infertility	INSL3 LGR8/GREAT
16687567	Maldescended testes, infertility, testicular dysgenesis syndrome	LGR8 receptor (R4H, W69R, and R72K)	Caucasi an from differ ent reg ions of Italy	1417 (967 subjects with a history of maldescended testes and/or infertility and/or testicular cancer, 450 controls)	Male infertility	INSL3 LGR8
15956751	Cryptorchidism				Male infertility	INSL3 LGR8/GREAT
15956751	Cryptorchidism				Male infertility	INSL3 LGR8/GREAT
15755855	Hypogonadotropic hypogonadism, testicular disorders			220 (135 andrologically well-characterized normal men, 85 patients with testicular disorders)	Male infertility
15533513	Familial cryptorchidism	One missense (A60T) substitution in exon 1 of INSL3 and two silent substitutions in exon 12 and one missense (I604V) substitution in exon 17 of GREAT		13 individuals with personal and family histories of cryptorchidism	Male infertiltiy	INSL3 LGR8/GREAT
15353080	Cryptorchidism			235 (135 ex-cryptorchid patients, 100 controls)	Male infertility	INSL3 LGR8/GREAT
15353080	Cryptorchidism			235 (135 ex-cryptorchid patients, 100 controls)	Male infertility	INSL3 LGR8/GREAT
12970298	Normozoospermia, complete azoospermia, bilateral cryptorchidism			167 (87 ex-cryptorchid patients, 80 controls)	Male infertility	INSL3 LGR8/GREAT
12601553	Cryptorchidism	exon 2, a heterozygous C/G substitution at nucleotide 2560 (N86K)		150 patients with idiopathic cryptorchidism	Male infertility
11992081	cryptorchidism			166 (118 boys with cryptorchidism, 48 normal controls)	Male infertility
11746019	Cryptorchidism				Male infertility
11383919	Cryptorchidism	G to A at position 27, 96, 126 and 178. Only the 178G-->A substitution changes codon 60 from alanine to threonine (A60T)		65 ex-cryptorchid patients	Male infertility
11380919	Cryptorchidism	G to A transition at position 178 of the INSL3 gene, which predicts an alanine (GCC) to threonine (ACC) change at codon 60 (designated A60T)	Japanes e	75 (70 controls, 5 sporadic bilateral cryptorchidism)	Male infertility
11182749	Maldescent of the testis	A-1G, V19L, P25S, A36T, R78H		211 (28 testicular maldescent, 24 patients with undermasculinised genitalia and intra-abdominal, 33 patients with inguinal gonads, 15 normal males, 29 males with undermasculinised genitalia and scrotal gonads, 82 females)	Male infertility
11095425	Cryptorchidism	R49X and P69L		181 145 formerly cryptorchid patients, 36 adult male controls()	Male infertility	INSL3/RLF
11095425	Cryptorchidism	R49X and P69L		181 145 formerly cryptorchid patients, 36 adult male controls()	Male infertility	INSL3/RLF
10759163	Cryptorchidism	G178A		30 (7 with familial form of cryptorchidism, 23 with sporadic cryptorchidism )	Male infertility
10729310	Cryptorchidism			31 bilateral cryptorchidism	Male infertility
10319319	Bilateral cryptorchidism				Male infertility
23100620	Important for testicular descent				Male infertility