Details for: MSH4

Gene ID: 4438

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: MSH4

Ensembl ID: ENSG00000057468

Description: mutS homolog 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • sst GABAergic cortical interneuron CL4023017
    CSI 7.32
    rCSI 9.43%
    PRS 92.09
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 4.5
    rCSI 5.59%
    PRS 90.02
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 2.14
    rCSI 6.68%
    PRS 93.04
  • L6b glutamatergic cortical neuron CL4023038
    CSI 1.89
    rCSI 5.89%
    PRS 92.07
  • retinal ganglion cell CL0000740
    CSI 1.7
    rCSI 3.75%
    PRS 91.84
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.63
    rCSI 6.15%
    PRS 91.39
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.38
    rCSI 2.31%
    PRS 91.66
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.37
    rCSI 3.32%
    PRS 89.97
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 1.3
    rCSI 7.67%
    PRS 91.57
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.21
    rCSI 4.36%
    PRS 90.2

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [MSH4](/details-gene/4438) (mutS homolog 4) is a protein-coding gene located on chromosome 1p31.1. As a member of the MutS family of DNA mismatch repair proteins, its primary and well-characterized function is in meiosis. It plays a crucial role in ensuring genomic stability during the formation of gametes by participating in processes such as `[Homologous chromosome pairing at meiosis](/details-go/GO:0007129)` and `[Reciprocal meiotic recombination](/details-go/GO:0007131)`. Consistent with this, bi-allelic mutations in [MSH4](/details-gene/4438) are associated with male and female infertility, including primary ovarian insufficiency ([108420](https://omim.org/entry/108420)) and non-obstructive azoospermia ([602105](https://omim.org/entry/602105)), as documented in several studies ([Link](https://doi.org/10.1093/hmg/ddx199), [Link](https://pubmed.ncbi.nlm.nih.gov/33437391/)). Interestingly, while its function is strongly linked to the germline, expression data from the **Overall** context reveals its highest significance in various neuronal subtypes, particularly `[sst GABAergic cortical interneuron](/details-cell/CL4023017)`, suggesting potential, uncharacterized roles in the central nervous system. ## Cellular Roles and Expression Landscape The established biological role of [MSH4](/details-gene/4438) is centered on gametogenesis in both sexes. Its involvement in `[Spermatogenesis](/details-go/GO:0007283)` and `[Female gamete generation](/details-go/GO:0007292)` is fundamental for reproductive fitness. Pathogenic variants disrupt meiotic progression, leading to meiotic arrest and subsequent infertility ([Link](https://doi.org/10.1186/s12958-022-00900-x), [Link](https://doi.org/10.1093/humrep/deab230)). The protein localizes to critical meiotic structures, including the `[Synaptonemal complex](/details-go/GO:0000795)` and `[Recombination nodule](/details-go/GO:0005713)`, where it functions to stabilize Holliday junction intermediates during crossover formation. In contrast to its well-defined meiotic function, a broad expression analysis in the **Overall** context highlights a significant and specific expression signature within the central nervous system. The gene shows the highest significance in neuronal populations, including: * `[sst GABAergic cortical interneuron](/details-cell/CL4023017)` (CSI: 7.32) * `[pvalb GABAergic cortical interneuron](/details-cell/CL4023018)` (CSI: 4.50) * `[chandelier pvalb GABAergic cortical interneuron](/details-cell/CL4023036)` (CSI: 2.14) * `[L6b glutamatergic cortical neuron](/details-cell/CL4023038)` (CSI: 1.89) * `[retinal ganglion cell](/details-cell/CL0000740)` (CSI: 1.70) This strong and specific expression pattern in diverse, terminally differentiated cortical neurons suggests that [MSH4](/details-gene/4438) may have a secondary, non-canonical function in the brain. Given its homology to DNA repair proteins, this role could be related to the maintenance of genomic integrity in long-lived, post-mitotic cells, a critical aspect of neuronal health. ## Pathways and Molecular Function The molecular functions of [MSH4](/details-gene/4438) are intrinsically linked to its role in DNA metabolism. As an ATP-dependent protein, it exhibits `[Atp binding](/details-go/GO:0005524)` and `[Mismatched dna binding](/details-go/GO:0030983)` activities, which are central to its function in recognizing and processing DNA structures during recombination. The gene is a key component of several fundamental biological pathways, as annotated by Reactome: * `[Meiosis](/details-pathway/R-HSA-1500620)` * `[Meiotic recombination](/details-pathway/R-HSA-912446)` * `[Reproduction](/details-pathway/R-HSA-1474165)` Its participation in the broader `[Cell cycle](/details-pathway/R-HSA-1640170)` pathway underscores its role in a highly specialized form of cell division. While these pathways are directly relevant to its function in germ cells, the molecular basis for its high expression in neurons is not yet elucidated and may involve an alternative application of its DNA binding and repair-related functions outside the context of meiotic recombination. ## Research Directions The striking discordance between the well-established meiotic function of [MSH4](/details-gene/4438) and its high expression significance in cortical neurons presents a compelling avenue for future research. This suggests either a novel, uncharacterized role for [MSH4](/details-gene/4438) in the mature brain or a previously unrecognized aspect of its regulation. **Proposed Testable Hypotheses:** 1. [MSH4](/details-gene/4438) performs a non-canonical function in post-mitotic neurons, contributing to the repair of DNA damage or the maintenance of genomic stability, which is essential for the longevity and function of these cells. 2. The high expression of [MSH4](/details-gene/4438) in specific neuronal subtypes is a remnant of a critical developmental role during neurogenesis, where it may have been involved in DNA recombination events related to neuronal diversity or differentiation. **Suggested Experimental Approach:** To test the hypothesis that [MSH4](/details-gene/4438) is involved in neuronal DNA repair, a conditional knockout mouse model could be developed to specifically delete [MSH4](/details-gene/4438) in a targeted neuronal population, such as somatostatin-positive interneurons (e.g., using an Sst-IRES-Cre driver line). Primary neuronal cultures from these mice could be exposed to genotoxic stress (e.g., radiation or chemical mutagens), and the efficiency of DNA repair could be quantified using assays like comet assays or immunostaining for DNA damage markers (e.g., γH2AX). Furthermore, *in vivo* analysis of aged conditional knockout mice could reveal long-term consequences of [MSH4](/details-gene/4438) deficiency on neuronal survival, synaptic plasticity, and cognitive function. **Therapeutic Potential:** Currently, the clinical relevance of [MSH4](/details-gene/4438) is primarily diagnostic. Genetic screening for pathogenic variants in [MSH4](/details-gene/4438) can provide a definitive diagnosis for certain cases of idiopathic infertility, such as non-obstructive azoospermia and primary ovarian insufficiency ([Link](https://doi.org/10.1038/s41436-020-0907-1)). Because these conditions result from a loss of function, therapeutic strategies would involve activation or gene replacement, which remain highly challenging and experimental. Inhibition of [MSH4](/details-gene/4438) is not a viable therapeutic approach. If a role in neuronal health and disease is established, its potential as a therapeutic target in neurodegenerative disorders could be explored, but this remains speculative.

Genular Protein ID: 151945567

Symbol: MSH4_HUMAN

Name: MutS protein homolog 4

UniProtKB Accession Codes:

O15457 Q5T4U6 Q8NEB3 Q9UNP8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CORUM 1 CTD 1 ChEBI 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 7 Ensembl 1 GO 15 Gene3D 3 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 5 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9299235

Title: Cloning and expression analysis of a meiosis-specific MutS homolog: the human MSH4 gene.

PubMed ID: 9299235

DOI: 10.1006/geno.1997.4857

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 28541421

Title: A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency.

PubMed ID: 28541421

DOI: 10.1093/hmg/ddx199

PubMed ID: 33437391

Title: A novel homozygous mutation in the meiotic gene MSH4 leading to male infertility due to non-obstructive azoospermia.

PubMed ID: 33437391

PubMed ID: 32741963

Title: Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.

PubMed ID: 32741963

DOI: 10.1038/s41436-020-0907-1

PubMed ID: 33448284

Title: Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals.

PubMed ID: 33448284

DOI: 10.1093/humrep/deaa362

PubMed ID: 34755185

Title: Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes.

PubMed ID: 34755185

DOI: 10.1093/humrep/deab230

PubMed ID: 35090489

Title: Novel bi-allelic MSH4 variants causes meiotic arrest and non-obstructive azoospermia.

PubMed ID: 35090489

DOI: 10.1186/s12958-022-00900-x

Sequence Information:

  • Length: 936
  • Mass: 104756
  • Checksum: 5A82684379346441
  • Sequence:
    • MLRPEISSTS PSAPAVSPSS GETRSPQGPR YNFGLQETPQ SRPSVQVVSA STCPGTSGAA 
GDRSSSSSSL PCPAPNSRPA QGSYFGNKRA YAENTVASNF TFGASSSSAR DTNYPQTLKT 
PLSTGNPQRS GYKSWTPQVG YSASSSSAIS AHSPSVIVAV VEGRGLARGE IGMASIDLKN 
PQIILSQFAD NTTYAKVITK LKILSPLEII MSNTACAVGN STKLFTLITE NFKNVNFTTI 
QRKYFNETKG LEYIEQLCIA EFSTVLMEVQ SKYYCLAAVA ALLKYVEFIQ NSVYAPKSLK 
ICFQGSEQTA MIDSSSAQNL ELLINNQDYR NNHTLFGVLN YTKTPGGSRR LRSNILEPLV 
DIETINMRLD CVQELLQDEE LFFGLQSVIS RFLDTEQLLS VLVQIPKQDT VNAAESKITN 
LIYLKHTLEL VDPLKIAMKN CNTPLLRAYY GSLEDKRFGI ILEKIKTVIN DDARYMKGCL 
NMRTQKCYAV RSNINEFLDI ARRTYTEIVD DIAGMISQLG EKYSLPLRTS FSSARGFFIQ 
MTTDCIALPS DQLPSEFIKI SKVKNSYSFT SADLIKMNER CQESLREIYH MTYMIVCKLL 
SEIYEHIHCL YKLSDTVSML DMLLSFAHAC TLSDYVRPEF TDTLAIKQGW HPILEKISAE 
KPIANNTYVT EGSNFLIITG PNMSGKSTYL KQIALCQIMA QIGSYVPAEY SSFRIAKQIF 
TRISTDDDIE TNSSTFMKEM KEIAYILHNA NDKSLILIDE LGRGTNTEEG IGICYAVCEY 
LLSLKAFTLF ATHFLELCHI DALYPNVENM HFEVQHVKNT SRNKEAILYT YKLSKGLTEE 
KNYGLKAAEV SSLPPSIVLD AKEITTQITR QILQNQRSTP EMERQRAVYH LATRLVQTAR 
NSQLDPDSLR IYLSNLKKKY KEDFPRTEQV PEKTEE