DUSP6

dual specificity phosphatase 6, the group of MAP kinase phosphatases

Basic information

Region (hg38): 12:89347234-89352501

Links

ENSG00000139318 ∙ NCBI:1848 ∙ OMIM:602748 ∙ HGNC:3072 ∙ Uniprot:Q16828 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 19 with or without anosmia (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 19, with or without anosmia	AD/Digenic	Endocrine	In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required	Audiologic/Otolaryngologic; Dental; Endocrine; Musculoskeletal; Neurologic	23643382
Relatively complex genetic models of disease have been described (eg, involving variants in other FGF8-network-associated genes)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DUSP6 gene.

• not provided (44 variants)
• Inborn genetic diseases (9 variants)
• Hypogonadotropic hypogonadism 19 with or without anosmia (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DUSP6 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				9	2	11
missense			18	1	3	22
nonsense	1					1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1		1	2
non coding				6	11	17
Total	1	0	18	16	16

Variants in DUSP6

This is a list of pathogenic ClinVar variants found in the DUSP6 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-89348954-T-C			Benign (Aug 09, 2018)
12-89349288-T-A		not specified	Uncertain significance (Dec 05, 2022)
12-89349305-G-A			Likely benign (Dec 24, 2018)
12-89349363-G-A		Hypogonadotropic hypogonadism 19 with or without anosmia	Likely benign (Sep 16, 2022)
12-89349425-C-T			Uncertain significance (Oct 22, 2019)
12-89349443-G-A		DUSP6-related disorder	Benign/Likely benign (Sep 07, 2022)
12-89349446-A-G			Benign (Jan 29, 2024)
12-89349446-A-A			Benign (Jan 31, 2024)
12-89349579-AAAGC-A			Likely benign (Sep 01, 2022)
12-89349812-G-A			Benign (Aug 09, 2018)
12-89349837-A-G			Benign (Aug 09, 2018)
12-89349860-G-A			Benign (Oct 18, 2020)
12-89350325-C-T			Likely benign (Nov 05, 2018)
12-89350469-T-G			Benign (Aug 09, 2018)
12-89350585-C-G			Uncertain significance (Aug 10, 2023)
12-89350602-G-T			Uncertain significance (Oct 01, 2023)
12-89350617-T-C		not specified	Uncertain significance (May 18, 2022)
12-89350679-G-A			Likely benign (Dec 18, 2023)
12-89350860-T-C		Hypogonadotropic hypogonadism 19 with or without anosmia	Uncertain significance (May 06, 2022)
12-89350881-G-A		Hypogonadotropic hypogonadism 19 with or without anosmia	Conflicting classifications of pathogenicity (Jan 12, 2024)
12-89350920-C-T		not specified	Uncertain significance (Aug 02, 2021)
12-89350964-C-T			Likely benign (Jun 05, 2022)
12-89350992-A-C			Uncertain significance (Dec 18, 2023)
12-89350996-A-C			Benign (Jan 29, 2024)
12-89351004-G-T			Uncertain significance (Aug 12, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DUSP6	protein_coding	protein_coding	ENST00000279488	3	6040

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.976	0.0239	125745	0	3	125748	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.22	166	216	0.767	0.0000102	2487
Missense in Polyphen		23	64.678	0.35561		765
Synonymous	-1.94	122	97.6	1.25	0.00000487	768
Loss of Function	3.14	0	11.5	0.00	4.97e-7	132

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.0000345	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Inactivates MAP kinases. Has a specificity for the ERK family (PubMed:9858808). Plays an important role in alleviating chronic postoperative pain. Necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery, which drives the resolution of acute postoperative allodynia (By similarity). Also important for dephosphorylation of MAPK1/3 in local wound tissue, which further contributes to resolution of acute pain (By similarity). {ECO:0000250|UniProtKB:Q9DBB1, ECO:0000269|PubMed:8670865}.
• Disease: DISEASE: Hypogonadotropic hypogonadism 19 with or without anosmia (HH19) [MIM:615269]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in DUSP6 also have a heterozygous mutation in another HH-associated gene including FGFR1 and SPRY4 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
• Pathway: Acute myeloid leukemia - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);EGF-Ncore;MAPK Signaling Pathway;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signal Transduction;Signaling by Interleukins;regulation of map kinase pathways through dual specificity phosphatases;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;Innate Immune System;Immune System;FGF;Nuclear Events (kinase and transcription factor activation);RAF-independent MAPK1/3 activation;ERKs are inactivated;Signaling by NTRK1 (TRKA);Signaling by NTRKs;ERK/MAPK targets;MAPK targets/ Nuclear events mediated by MAP kinases;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;ErbB1 downstream signaling;MyD88 dependent cascade initiated on endosome;Negative regulation of MAPK pathway;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;Signaling by Receptor Tyrosine Kinases;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;FGF signaling pathway (Consensus)

Recessive Scores

• pRec: 0.373

Intolerance Scores

• loftool: 0.0680
• rvis_EVS: 0.1
• rvis_percentile_EVS: 61.49

Haploinsufficiency Scores

• pHI: 0.383
• hipred: Y
• hipred_score: 0.825
• ghis: 0.442

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Dusp6
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; immune system phenotype; skeleton phenotype; hearing/vestibular/ear phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: dusp6
• Affected structure: Mauthner neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: MAPK cascade;activation of MAPK activity;inactivation of MAPK activity;protein dephosphorylation;response to organic cyclic compound;cell differentiation;peptidyl-tyrosine dephosphorylation;response to drug;positive regulation of apoptotic process;response to nitrosative stress;regulation of heart growth;negative regulation of ERK1 and ERK2 cascade;response to growth factor
• Cellular component: nucleoplasm;cytoplasm;cytosol
• Molecular function: protein tyrosine phosphatase activity;protein tyrosine/serine/threonine phosphatase activity;MAP kinase tyrosine/serine/threonine phosphatase activity