MSH4 (mutS homolog 4)

Gene

• Entrez ID: 4438
• Gene name: MutS homolog 4
• Gene symbol: MSH4
• Synonyms (NCBI Gene): ASG, POF20, SPGF2
• Chromosome: 1
• Chromosome location: 1p31.1
• Summary: This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000166	Function	Nucleotide binding	IEA
GO:0000793	Component	Condensed chromosome	IEA
GO:0000794	Component	Condensed nuclear chromosome	IEA
GO:0000795	Component	Synaptonemal complex	IEA
GO:0001541	Process	Ovarian follicle development	IEA
GO:0003677	Function	DNA binding	IEA
GO:0003677	Function	DNA binding	TAS	9299235
GO:0003690	Function	Double-stranded DNA binding	IBA
GO:0005515	Function	Protein binding	IPI	16397227, 22401567, 23725059
GO:0005524	Function	ATP binding	IEA
GO:0005634	Component	Nucleus	IBA
GO:0005634	Component	Nucleus	IEA
GO:0005634	Component	Nucleus	TAS	9299235
GO:0005694	Component	Chromosome	IEA
GO:0005694	Component	Chromosome	ISS
GO:0005713	Component	Recombination nodule	IEA
GO:0006298	Process	Mismatch repair	IEA
GO:0007129	Process	Homologous chromosome pairing at meiosis	IEA
GO:0007131	Process	Reciprocal meiotic recombination	IBA
GO:0007131	Process	Reciprocal meiotic recombination	TAS	9299235
GO:0007283	Process	Spermatogenesis	IEA
GO:0007292	Process	Female gamete generation	IEA
GO:0030983	Function	Mismatched DNA binding	IEA
GO:0051321	Process	Meiotic cell cycle	IEA
GO:0051321	Process	Meiotic cell cycle	IEA
GO:0140664	Function	ATP-dependent DNA damage sensor activity	IEA

Other IDs

• MIM: 602105
• HGNC: 7327
• e!Ensembl: ENSG00000057468

Protein

• UniProt ID: O15457
• Protein name: MutS protein homolog 4 (hMSH4)
• Protein function: Involved in meiotic recombination. Required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis.
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF05188	MutS_II	155 → 298	MutS domain II	Domain
  PF05192	MutS_III	315 → 627	MutS domain III	Domain
  PF05190	MutS_IV	493 → 587	MutS family domain IV	Domain
  PF00488	MutS_V	676 → 869	MutS domain V	Domain

• Tissue specificity: TISSUE SPECIFICITY: Highly expressed in testis (PubMed:33437391, PubMed:9299235). Also expressed in the ovary (PubMed:9299235). {ECO:0000269|PubMed:33437391, ECO:0000269|PubMed:9299235}.
• Sequence:

  MLRPEISSTSPSAPAVSPSSGETRSPQGPRYNFGLQETPQSRPSVQVVSASTCPGTSGAA
  GDRSSSSSSLPCPAPNSRPAQGSYFGNKRAYAENTVASNFTFGASSSSARDTNYPQTLKT
  PLSTGNPQRSGYKSWTPQVGYSASSSSAISAHSPSVIVAVVEGRGLARGEIGMASIDLKN
  PQIILSQFADNTTYAKVITKLKILSPLEIIMSNTACAVGNSTKLFTLITENFKNVNFTTI
  QRKYFNETKGLEYIEQLCIAEFSTVLMEVQSKYYCLAAVAALLKYVEFIQNSVYAPKSLK
  ICFQGSEQTAMIDSSSAQNLELLINNQDYRNNHTLFGVLNYTKTPGGSRRLRSNILEPLV
  DIETINMRLDCVQELLQDEELFFGLQSVISRFLDTEQLLSVLVQIPKQDTVNAAESKITN
  LIYLKHTLELVDPLKIAMKNCNTPLLRAYYGSLEDKRFGIILEKIKTVINDDARYMKGCL
  NMRTQKCYAVRSNINEFLDIARRTYTEIVDDIAGMISQLGEKYSLPLRTSFSSARGFFIQ
  MTTDCIALPSDQLPSEFIKISKVKNSYSFTSADLIKMNERCQESLREIYHMTYMIVCKLL
  SEIYEHIHCLYKLSDTVSMLDMLLSFAHACTLSDYVRPEFTDTLAIKQGWHPILEKISAE
  KPIANNTYVTEGSNFLIITGPNMSGKSTYLKQIALCQIMAQIGSYVPAEYSSFRIAKQIF
  TRISTDDDIETNSSTFMKEMKEIAYILHNANDKSLILIDELGRGTNTEEGIGICYAVCEY
  LLSLKAFTLFATHFLELCHIDALYPNVENMHFEVQHVKNTSRNKEAILYTYKLSKGLTEE
  KNYGLKAAEVSSLPPSIVLDAKEITTQITRQILQNQRSTPEMERQRAVYHLATRLVQTAR
  NSQLDPDSLRIYLSNLKKKYKEDFPRTEQVPEKTEE

• Sequence length: 936

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Genetic non-acquired premature ovarian failure	Likely pathogenic; Pathogenic	rs116141807, rs557796016, rs1430228393, rs777079867, rs1386320504, rs771456188	RCV001661757 RCV001661761 RCV001661772 RCV001663387 RCV001663388 RCV001663389	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Non-obstructive azoospermia	Likely pathogenic; Pathogenic	rs377712900, rs1651856824, rs751781089, rs149042353	RCV001255224 RCV001281660 RCV001281661 RCV001281662	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Oligospermia	Likely pathogenic; Pathogenic	rs377712900	RCV001255223	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Premature ovarian failure 20	Pathogenic; Likely pathogenic	rs774501542, rs377712900, rs149042353	RCV002260906 RCV002260684 RCV002264776	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Premature ovarian insufficiency	Likely pathogenic; Pathogenic	rs377712900	RCV001201398	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Spermatogenic failure 2	Pathogenic; Likely pathogenic	rs1386320504, rs2100570734, rs2100513927, rs149910287, rs2100581757, rs377712900, rs149042353	RCV002260707 RCV002260907 RCV002260908 RCV002260909 RCV002260910 RCV002260683 RCV002264775	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
GONADAL DYSGENESIS, 46,XX	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
OVARIAN FAILURE, PREMATURE	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TESTICULAR AZOOSPERMIA	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Anaplastic astrocytoma	Anaplastic Astrocytoma	BEFREE	25041856		★☆☆☆☆ Found in Text Mining only
Anodontia	Anodontia	Pubtator	37162286	Associate	★☆☆☆☆ Found in Text Mining only
Astrocytoma	Astrocytoma	Pubtator	25041856	Associate	★☆☆☆☆ Found in Text Mining only
Azoospermia	Azoospermia	BEFREE	30247578		★☆☆☆☆ Found in Text Mining only
Azoospermia	Azoospermia	Pubtator	35090489	Associate	★☆☆☆☆ Found in Text Mining only
Azoospermia Nonobstructive	Nonobstructive azoospermia	Pubtator	20075417	Associate	★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	19781088		★☆☆☆☆ Found in Text Mining only
Breast Neoplasms	Breast neoplasm	Pubtator	19781088	Associate	★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	31127692	Associate	★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms Hereditary Nonpolyposis	Lynch syndrome	Pubtator	37162286	Associate	★☆☆☆☆ Found in Text Mining only
Distal myopathy Nonaka type	Distal myopathy	Pubtator	35090489	Associate	★☆☆☆☆ Found in Text Mining only
Down Syndrome	Down syndrome	Pubtator	28627638	Associate	★☆☆☆☆ Found in Text Mining only
Glioblastoma	Glioblastoma	BEFREE	25041856		★☆☆☆☆ Found in Text Mining only
Glioblastoma	Glioblastoma	Pubtator	25041856	Associate	★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	Pubtator	25041856	Associate	★☆☆☆☆ Found in Text Mining only
Infertility	Infertility	Pubtator	18706547	Associate	★☆☆☆☆ Found in Text Mining only
Infertility Male	Male infertility	Pubtator	18706547	Associate	★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	19781088		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of prostate	Prostate cancer	BEFREE	27550944		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	27550944		★☆☆☆☆ Found in Text Mining only
Mesothelioma Malignant	Mesothelioma	Pubtator	34008015	Associate	★☆☆☆☆ Found in Text Mining only
Micropenis	Micropenis	BEFREE	17283037		★☆☆☆☆ Found in Text Mining only
Neurilemmoma	Neurilemmoma	BEFREE	25041856		★☆☆☆☆ Found in Text Mining only
Ovarian Diseases	Ovarian diseases	Pubtator	37620942	Associate	★☆☆☆☆ Found in Text Mining only
Ovarian Failure, Premature	Ovarian Failure	BEFREE	18166824, 28541421		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Penis agenesis	Penis Agenesis	BEFREE	17283037		★☆☆☆☆ Found in Text Mining only
Premature Menopause	Premature Menopause	BEFREE	18166824, 28541421		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic Neoplasms	BEFREE	27550944		★☆☆☆☆ Found in Text Mining only
Sarcoglycanopathies	Sarcoglycanopathies	Pubtator	9192266	Associate	★☆☆☆☆ Found in Text Mining only
Testicular Neoplasms	Testicular Neoplasms	BEFREE	24803180		★☆☆☆☆ Found in Text Mining only
Urinary Bladder Neoplasms	Urinary bladder neoplasms	Pubtator	32221012, 36076047	Associate	★☆☆☆☆ Found in Text Mining only