MSX1
protein-codingmsh homeobox 1, the group of NKL subclass homeoboxes and pseudogenes
Gene summary
This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia. [provided by RefSeq, Jul 2008]
- HOX7
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007129
Submitter: ClinGen
MSX1 was first reported in relation to autosomal dominant tooth agenesis, selective, 1 in 1996 (Vastardis et al., PMID: 8696335). MSX1 has been noted to be associated with the following disease entities: Orofacial cleft 5 (OMIM:608874), Tooth agenesis, selective, 1, with or without orofacial cleft (OMIM:106600) and Ectodermal dysplasia 3, Witkop type (OMIM:189500). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in phenotypic variability therefore, Ectodermal dysplasia 3, Witkop type (OMIM:189500) was split. Whereas, the following disease entities Orofacial cleft 5 (OMIM:608874) and Tooth agenesis, selective, 1, with or without orofacial cleft (OMIM:106600) have been lumped into one disease entity, tooth agenesis, selective, 1 (MONDO:0007129). The split disease entity will be curated separately. This curation is for the lumped entity autosomal dominant tooth agenesis, selective, 1. Ten variants (5 missense, 4 nonsense, 1 frameshift) that have been reported in 10 probands in 6 publications (PMID: 8696335, 12097313, 15264286, 33419968, 10742093, 22813217) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by experimental evidence such as protein-protein interaction and expression level evidence (PMID: 16651263, 16651263). Additionally, MSX1 knockout mice had phenotypes including cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development (PMID: 7914451). In summary, MSX1 is definitively associated with autosomal dominant tooth agenesis, selective, 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 10/19/23 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0008582
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012142
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008582
Submitter: ClinGen
*MSX1* was first reported in relation to autosomal dominant tooth and nail syndrome in 2001 (Jumlongras et al., PMID: 11369996). *MSX1* has been noted to be associated with the following disease entities: Orofacial cleft 5 (OMIM:608874), Tooth agenesis, selective, 1, with or without orofacial cleft (OMIM:106600) and Ectodermal dysplasia 3, Witkop type (OMIM:189500). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in phenotypic variability therefore, Ectodermal dysplasia 3, Witkop type (OMIM:189500) also known as tooth and nail syndrome was split. Whereas, the following disease entities Orofacial cleft 5 (OMIM:608874) and Tooth agenesis, selective, 1, with or without orofacial cleft (OMIM:106600) have been lumped into one disease entity, tooth agenesis, selective, 1 (MONDO:0007129). This curation is for the split entity autosomal dominant tooth and nail syndrome. Three variants (1 nonsense, 1 3’UTR, 1 missense) that have been reported in 3 probands in 3 publications (PMIDs: 11369996, 24031111, 33708320) are included in this curation. However, the genetic evidence was not scored due to uncertainty of phenotypes illustrated in the study, frequency of variants and/or poor in silico scores. The mechanism of pathogenicity is unknown. This gene-disease association is supported by experimental evidence including expression in the nail bed and hair follicles of mice (PMID: 7538067) and an *MSX1* knockout mice showing defective nail plates (PMID: 11369996). In summary, the evidence supporting the relationship between *MSX1* and autosomal dominant tooth and nail syndrome has been disputed and no valid genetic evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *MSX1* plays in this disease.This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting dates 10/19/23 and 02/08/2024 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0008582
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005486
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007129
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007129
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Dermatologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MSX1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002448.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 24 | 1 | 25 | |||
| missense | 4 | 3 | 93 | 14 | 2 | 116 |
| nonsense | 6 | 4 | 1 | 11 | ||
| start loss | 0 | |||||
| frameshift | 13 | 3 | 2 | 18 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 23 | 11 | 96 | 38 | 3 | 171 |
Highest pathogenic variant AF is 0.000026036178
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002439.2 | 2 | MANE Select | |
| Ensembl | ENSP00000372170.4 | 2 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| msx1a | Danio rerio | Structure: ceratobranchial cartilage Quality: shortened abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HTLV-I infection - Homo sapiens (human)
- Neural Crest Differentiation
- Dopaminergic Neurogenesis
- Prader-Willi and Angelman Syndrome
Biological Process
- negative regulation of transcription by RNA polymerase II
- cell morphogenesis
- in utero embryonic development
- epithelial to mesenchymal transition involved in endocardial cushion formation
- muscle organ development
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- p53 binding
Cellular Component
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000382723
- Coding exons
- 2
- Length
- 4271
- Individuals with no LoFs
- 124097
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 124100
- p
- 0.0000121
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.278 | 158 | 168 | 0.940 | 0.0000100 | 1870 |
| Missense (PolyPhen) | 40 | 66.307 | 0.60325 | 690 | ||
| Synonymous | -1.45 | 97 | 80.5 | 1.21 | 0.00000492 | 669 |
| Loss of Function | 1.57 | 2 | 6.22 | 0.321 | 2.65e-7 | 80 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000064 | 0.000064 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000020 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a transcriptional repressor. May play a role in limb-pattern formation. Acts in cranofacial development and specifically in odontogenesis. Expression in the developing nail bed mesenchyme is important for nail plate thickness and integrity. {ECO:0000269|PubMed:11369996, ECO:0000269|PubMed:12807959}.;
- Disease
- DISEASE: Tooth agenesis, selective, 1 (STHAG1) [MIM:106600]: A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). STHAG1 can be associated with orofacial cleft in some patients. {ECO:0000269|PubMed:12097313, ECO:0000269|PubMed:8696335}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=MSX1 is deleted in some patients with Wolf- Hirschhorn syndrome (WHS). WHS results from sub-telomeric deletions in the short arm of chromosome 4. {ECO:0000305|PubMed:1969845}.; DISEASE: Ectodermal dysplasia 3, Witkop type (ECTD3) [MIM:189500]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD3 is characterized by abnormalities largely limited largely to teeth (some of which are missing) and nails (which are poorly formed early in life, especially toenails). This condition is distinguished from anhidrotic ectodermal dysplasia by autosomal dominant inheritance and little involvement of hair and sweat glands. The teeth are not as severely affected. {ECO:0000269|PubMed:11369996}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Non-syndromic orofacial cleft 5 (OFC5) [MIM:608874]: A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. {ECO:0000269|PubMed:12807959}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.606
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |