MKS1
protein-codingMKS transition zone complex subunit 1, the group of MKS complex|B9 domain containing
Gene summary
The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
- MKS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~14.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009571
Submitter: Myriad Women's Health
Inheritance Pattern: Unknown
Disease ID:MONDO:0014441
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014441
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014928
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: ClinGen
MKS1 was first reported in relation to autosomal recessive Meckel Syndrome (MKS) in 2006 (Kyttala et al., PMID: 16415886). Additionally, MKS1 was initially associated with Bardet-Biedl Syndrome (BBS) in 2008 (Leitch et al., PMID: 18327255) and with Joubert Syndrome (JS) in 2014 (Romani et al., PMID: 24886560). Typical features of MKS include cystic kidneys, occipital encephalocele, and polydactyly. BBS patients also commonly present with polydactyly, while also showing obesity and retinitis pigmentosa. Finally, JS is characterized by cerebellar vermis hypoplasia, cystic kidney disease, liver fibrosis, polydactyly, and/or retinal dystrophy. Each of these diseases is considered a ciliopathy, as pathogenic mutations in MKS1 cause primary cilia dysfunction in affected individuals. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found no difference in inheritance pattern between these three disorders, and phenotypic variability between them was considered within the spectrum of a single disease. Therefore, Meckel syndrome 1 (MIM#: 249000), Bardet-Biedl syndrome 13 (MIM#: 615990) and Joubert syndrome 28 (MIM#: 617121) have been lumped into a single curation under the name ciliopathy-MKS1. Fifteen variants (four splicing, three nonsense, five missense, two in-frame deletions, and one frameshift deletion) that have been reported in ten probands in seven publications (PMIDs: 24886560, 33193692, 34359301, 26490104, 18327255, 24608809, 17397051) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. Although unclear, the mechanism of pathogenicity may be a spectrum, with biallelic truncating mutations in MKS1 leading to MKS and less damaging mutations causing BBS or JS. Of note, a recurrent splice-altering pathogenic variant NM_017777.4(MKS1): c.1408-34_1408-6del (ClinVar ID: 188400) was initially described as a founder mutation causing MKS in the Finnish population and is prevalent in many other mostly European populations (PMID: 16415886, 17377820). This gene-disease association is also supported by expression studies in mouse embryos showing that MKS1 expression is prominent in tissues showing MKS-characteristic malformations: brain, liver, kidney and digits of the upper limbs, with intense proximal tubule staining in the human fetus (PMID: 16415886, 17185389). The MKS1 protein localizes to the cilia transition zone, supporting the role of MKS1 in ciliary function and co-immunoprecipitation experiments showed that the MKS1 protein interacts with TMEM67, a protein also associated with MKS. Finally, using RNAi to silence MKS1 expression, it has been shown that ciliary formation and cilia length were significantly decreased in targeted cells when compared to control cells (PMID: 17185389). Confirming these results, Weatherbee et. al. showed that primary cilia formation is reduced in mesenchymal and epithelial tissues of Mks1-knockout mice. This publication goes on to provide evidence that mutant mice recapitulate the main features seen in human MKS patients, including polydactyly, cystic kidneys, and occipital encephalocele (PMID: 19776033). A second Mks1-null mouse model similarly recapitulates these primary human MKS features (PMID: 23454480). In summary, MKS1 is definitively associated with autosomal recessive ciliopathy- MKS1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on September 5, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0016364
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014441
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009571
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0018772
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018921
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Endocrine
Rationale: Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MKS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017777.4. 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 | 1 | 24 | 242 | 267 | ||
| missense | 4 | 9 | 375 | 19 | 407 | |
| nonsense | 23 | 33 | 1 | 57 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 36 | 37 | 5 | 78 | ||
| splice donor/acceptor (+/-2bp) | 6 | 50 | 4 | 60 | ||
| Total | 72 | 130 | 409 | 261 | 0 | 872 |
Highest pathogenic variant AF is 0.0011076444
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060247.2 | 18 | MANE Select | |
| Ensembl | ENSP00000376827.2 | 18 | MANE Select | |
| RefSeq | NP_001308197.1 | 13 | Standard | |
| RefSeq | NP_001308198.1 | 17 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mks1 | Danio rerio | Structure: whole organism Quality: decreased life span abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ectoderm Differentiation
- Anchoring of the basal body to the plasma membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- neural tube closure
- smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation
- determination of left/right symmetry
- epithelial structure maintenance
- embryonic digit morphogenesis
Molecular Function
- protein binding
Cellular Component
- cytoplasm
- centrosome
- centriole
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000393119
- Coding exons
- 18
- Length
- 14164
- Individuals with no LoFs
- 124690
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 120
- Defined
- 124810
- p
- 0.000481
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.492 | 296 | 321 | 0.923 | 0.0000212 | 3629 |
| Missense (PolyPhen) | 70 | 82.065 | 0.85298 | 904 | ||
| Synonymous | 0.0624 | 123 | 124 | 0.993 | 0.00000799 | 1084 |
| Loss of Function | 1.35 | 29 | 37.9 | 0.764 | 0.00000228 | 405 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00039 | 0.00039 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0017 | 0.0017 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00035 | 0.00035 | rare |
| South Asian | 0.0010 | 0.0010 | notable |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Involved in centrosome migration to the apical cell surface during early ciliogenesis. Required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Required for cell branching morphology. {ECO:0000269|PubMed:17185389, ECO:0000269|PubMed:19515853, ECO:0000269|PubMed:26490104}.;
- Disease
- DISEASE: Meckel syndrome 1 (MKS1) [MIM:249000]: A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. {ECO:0000269|PubMed:16415886, ECO:0000269|PubMed:19466712, ECO:0000269|PubMed:26490104}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bardet-Biedl syndrome 13 (BBS13) [MIM:615990]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:18327255}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 28 (JBTS28) [MIM:617121]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS28 inheritance is autosomal recessive. {ECO:0000269|PubMed:24886560}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.357
Intolerance Scores
- LoFtool
- 0.974
- RVIS EVS
- -0.04
- RVIS percentile EVS
- 50.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.891
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |