Alternative titles; symbols
HGNC Approved Gene Symbol: MKS1
Cytogenetic location: 17q22 Genomic coordinates (GRCh38) : 17:58,205,441-58,219,255 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q22 | Bardet-Biedl syndrome 13 | 615990 | Autosomal recessive | 3 |
| Joubert syndrome 28 | 617121 | Autosomal recessive | 3 | |
| Meckel syndrome 1 | 249000 | Autosomal recessive | 3 |
MKS1 belongs to a small family of B9 domain-containing proteins that also includes B9D1 (614144) and B9D2 (611951), and all 3 B9 domain-containing proteins associate with basal bodies and primary cilia in mammalian cells (summary by Bialas et al., 2009).
Kyttala et al. (2006) identified the MKS1 gene (FLJ20345) in a 100-kb region of chromosome 17q23 to which Meckel syndrome had been linked in Finnish families. The gene contains an open reading frame (bp 76-1755) coding for a 559-amino acid polypeptide containing a conserved B9 domain. Comparison of sequence across human, mouse, zebrafish, fruit fly, and C. elegans showed high conservation. Human and mouse coding regions are 86 to 88% similar at the nucleotide level and 89% at the amino acid level. In situ hybridization analyses showed a relatively broad tissue expression of Mks1 in mouse embryo at embryonic day 15.5. The expression was especially prominent in tissues showing malformations characteristic of Meckel syndrome: brain, liver, kidney, and digits of the upper limbs. Highest expression was observed in bronchiolar epithelium. Hypoplastic lungs are frequently reported in MKS patients, but this feature had been presumed to be caused by lack of amniotic fluid and mechanical pressure from the enlarged kidneys.
By immunohistochemical analysis of 18- to 20-week-old human fetal kidneys, Dawe et al. (2007) found moderate to high expression of meckelin (MKS3, or TMEM67; 609884) and MKS1 at the proximal renal tubule epithelia, but not at glomeruli. In liver, these proteins were expressed at the biliary epithelium of larger bile ducts, but not in hepatocytes. In biliary epithelial cells, MKS1 showed a clear punctate doublet staining pattern characteristic of a centrosomal localization. In HEK293 cells, MKS1 showed a broad intracellular localization with occasional distribution at the cell border. Western blot analysis detected MKS1 at an apparent molecular mass of 70 kD.
Using RNA interference, Dawe et al. (2007) found that knockdown of either Mks1 or Mks3 in mouse inner medullary IMCD-3 cells blocked centriole migration to the apical membrane and formation of the primary cilium. Coimmunoprecipitation experiments showed that wildtype Mks1 and Mks3 interacted, and knockdown of either Mks1 or Mks3 in IMCD-3 cells decreased the formation of highly branched structures and tubules in 3-dimensional cultures. Dawe et al. (2007) concluded that MKS1 and MKS3 have roles in ciliogenesis and renal tubulogenesis.
Tammachote et al. (2009) showed that kidney tissue and cells from MKS1 and MKS3 (607361) patients showed defects in centrosome and cilia number, including multiciliated respiratory-like epithelia, and longer cilia. Stable shRNA knockdown of Mks1 and Mks3 in IMCD-3 cells induced multiciliated and multicentrosomal phenotypes. MKS1 and MKS3 functions are required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Tammachote et al. (2009) concluded that MKS1 and MKS3 are ciliopathies, with new cilia-related eye and sperm phenotypes defined.
Williams et al. (2011) showed that the conserved proteins Mks1, Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67, Rpgrip1l (610937), Cc2d2a (612013), Nphp1 (607100), and Nphp4 (607215) functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.
Using tandem affinity purification and mass spectrometry to isolate proteins that purified with B9d1 (614144) in mouse IMCD3 cells and embryonic fibroblasts, Chih et al. (2012) identified several components of the B9d1-containing ciliary complex, including Tmem231 (614949), Tmem17 (614950), B9d2 (611951), Tctn1 (609863), Tctn2 (613846), Mks1, Ahi1 (608894), Cc2d2a (612013), and Kctd10 (613421).
Kyttala et al. (2006) determined that the 14-kb MKS1 gene contains 18 exons.
Kyttala et al. (2006) stated that the FLJ20345 gene (MKS1 gene) is on chromosome 17q23. The mouse homolog maps to a region of chromosome 11 demonstrating homology of synteny with human 17q23.
Gross (2015) mapped the MKS1 gene to chromosome 17q22 based on an alignment of the MKS1 sequence (GenBank BC010061) with the genomic sequence (GRCh38).
Using database analysis, Bialas et al. (2009) found orthologs of B9D1, B9D2, and MKS1 in the vast majority of ciliated species, but not in nonciliated organisms. The 3 B9 domain-containing proteins appeared to be evolutionarily ancient, and the duplications resulting in the 3 protein clades preceded speciation.
Meckel Syndrome 1
Meckel syndrome (MKS) is a severe autosomal recessive fetal developmental disorder. The clinical hallmarks are occipital meningoencephalocele, cystic kidney dysplasia, fibrotic changes of the liver, and polydactyly. Genetic heterogeneity was established by genome linkage scans. The MKS1 locus on 17q (249000) was identified in Finnish families. Kyttala et al. (2006) found that in Finnish families in which the MKS1 locus was identified, 70% of the patients were homozygous for the same haplotype on 17q23. Sequence analysis of the MKS1 gene showed a 29-bp deletion in intron 15 (609883.0001) in 3 Finnish families sharing the MKS1 haplotype and in 1 German patient with evidence of linkage to 17q23. This deletion was located only 4 bp away from the splice acceptor site and was predicted to interrupt the splice branching site. The intronic deletion was detected as a size difference in PCR products from genomic DNA, and analysis of DNA samples of 26 Finnish families with the common founder haplotype confirmed that all individuals were homozygous, and that parents were heterozygous, for this deletion. Comparative genomics and proteomics data implicated MKS1 in ciliary function. Review of the series of 67 Finnish MKS patients reported by Salonen (1984) showed 3 cases with situs inversus totalis (see 270100), which implied an increased risk for this rare condition in Meckel syndrome and would provide another link to ciliary dysfunction.
Consugar et al. (2007) identified mutations in the MKS1 gene in affected individuals in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All 5 families had the major Finnish deletion mutation: 2 were homozygous, and 3 were compound heterozygous with another pathogenic mutation (609883.0004 and 609883.0005).
Bardet-Biedl Syndrome 13
Leitch et al. (2008) demonstrated that mutations in MKS1, MKS3 (609884), and CEP290 (610142) either can cause Bardet-Biedl syndrome (see 209900) or may have a potential epistatic effect on mutations in known BBS-associated loci. Five of 6 families with both MKS1 and BBS mutations manifested seizures, a feature that is not a typical component of either Meckel or Bardet-Biedl syndrome. Functional studies in zebrafish showed that mks1 is necessary for gastrulation movements and that it interacts genetically with known bbs genes. In 1 patient compound heterozygous mutations in MKS1 resulting in the BBS phenotype were found (see 609883.0006). In 5 families a single heterozygous mutation in MKS1 was found. Two of these families also carried mutations in BBS10 (610148), and a third family carried a homozygous mutation in BBS1 (209901). Leitch et al. (2008) concluded that their data extended the genetic stratification of ciliopathies and suggested that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum.
In a Chinese boy with BBS13, Xing et al. (2014) identified compound heterozygous missense mutations in the MKS1 gene (Y461C; 609883.0008) and R534Q (609883.0009). The mutations were identified by high-throughput targeted exome sequencing of 144 known genes responsible for inherited retinal diseases. Functional studies of the variants were not performed.
Joubert Syndrome 28
In 2 unrelated patients with Joubert syndrome-28 (JBTS28; 617121), Romani et al. (2014) identified biallelic mutations in the MKS1 gene (609883.0010-609883.0012). Functional studies of the variants and studies of patient cells were not performed. The patients were part of a group of 260 JBTS patients who were screened for mutations in ciliopathy genes.
Weatherbee et al. (2009) showed that loss of function of mouse Mks1 resulted in an accurate model of Meckel syndrome, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development, and the kidney. In contrast to cell culture studies, loss of Mks1 in vivo did not interfere with apical localization of epithelial basal bodies, but rather led to defective cilia formation in most, but not all, tissues. Analysis of patterning in the neural tube and the limb demonstrated altered Hedgehog (Hh) pathway signaling underlying some MKS defects, although both tissues showed an expansion of the domain of response to Shh (600725) signaling, unlike the phenotypes seen in other mutants with cilia loss. Other defects in the skull, lung, rib cage, and long bones were thought likely to be the result of disruption of Hh signaling. Weatherbee et al. (2009) concluded that disruption of Hh signaling may explain many, but not all, of the defects caused by loss of Mks1.
Bialas et al. (2009) disrupted the B9 domains of C. elegans mks1, mksr1, and mksr2. In contrast to the defect found in mouse cells, C. elegans expressing single, double, or triple mks/mksr mutants showed no overt defects in ciliary structure, nor in intraflagellar transport, chemosensation, osmosensation, or lipid accumulation. However, disruption of one B9 domain-containing protein resulted in mislocalization of the others, and all possible double mks/mksr mutant combinations altered insulin signaling, leading to increased life span. The mks1/mksr1/mksr2 triple mutant did not exhibit a longevity phenotype.
In 3 Finnish families sharing the founder MKS1 haplotype and in 1 German patient with evidence of linkage of Meckel syndrome to 17q23 (MKS1; 249000), Kyttala et al. (2006) found that the MKS1 gene showed a 29-bp deletion in intron 15 as the cause of the anomaly. This deletion was located only 4 bp away from the splice acceptor site and probably interrupted the splice branching site. The same intronic deletion was found in 26 Finnish families with a common founder haplotype; all affected individuals were homozygous, and the parents heterozygous, for the deletion, which Kyttala et al. (2006) called the MKS1-Fin(major) mutation. This mutation was also found in an American family and in a family of mixed Swedish-Portuguese-Irish descent.
Auber et al. (2007) identified the 29-bp deletion in intron 15 of the MKS1 gene in 8 of 20 unrelated fetuses diagnosed clinically with MKS. Six cases, consisting of 1 heterozygous and 5 homozygous mutations, had the campomelic variant of the disorder. The carrier frequency of this mutation in the German population was determined to be 1 in 260.
In a case of Meckel syndrome (MKS1; 249000) of German ancestry, Kyttala et al. (2006) found compound heterozygosity for mutations in MKS1 located at the very beginning of the transcript: a 5-bp insertion in exon 1 (50insCCGGG), causing a frameshift (Pro17fsTer163); and a T-to-C substitution at the splice donor site of intron 1 (IVS1+2T-C; 609883.0003).
For discussion of the splice site mutation in intron 1 of the MKS1 gene (IVS1+2T-C) that was found in compound heterozygous state in a patient with Meckel syndrome (MKS1; 249000) by Kyttala et al. (2006), see 609883.0002.
In a 16-week-old fetus with Meckel syndrome (MKS1; 249000) diagnosed by ultrasound, Consugar et al. (2007) identified compound heterozygosity for 2 mutations in the MKS1 gene: a G-to-A transition in intron 11 (IVS11+1G-A), resulting in a splice site mutation inherited from the African American mother, and the major Finnish mutation (609883.0001) inherited from the Caucasian father.
In 2 unrelated fetuses with Meckel syndrome (MKS1; 249000), Consugar et al. (2007) identified compound heterozygosity for 2 mutations in the MKS1 gene: a 417G-A transition in exon 4 and the major Finnish mutation (609883.0001). The families were of Dutch and German origin, respectively. RT-PCR and direct sequencing showed that the 417G-A change resulted in abnormal splicing and deletion of exon 4.
In a 2-year-old child of Turkish descent with Bardet-Biedl syndrome-13 (BBS13; 615990), Leitch et al. (2008) identified compound heterozygosity for mutations in the MKS1 gene: a cys492-to-trp (C492W) substitution, and a 3-bp deletion that removes a phenylalanine (F371del; 609883.0007). Neither mutation was found in 192 control chromosomes, and the patient did not have mutations in any of the 12 theretofore known BBS genes. The patient had obesity, polydactyly, and nystagmus but had not yet manifested retinitis pigmentosa.
For discussion of the 3-bp deletion in the MKS1 gene resulting in deletion of phenylalanine (F371del) that was found in compound heterozygous state in a patient with Bardet-Biedl syndrome-13 (BBS13; 615990) by Leitch et al. (2008), see 609883.0006.
In a Chinese boy (RP467) with Bardet-Biedl syndrome-13 (BBS13; 615990), Xing et al. (2014) identified compound heterozygous mutations in the MKS1 gene: a c.1382A-G transition, resulting in a tyr461-to-cys (Y461C) substitution, and a c.1601G-A transition, resulting in an arg534-to-gln (R534Q; 609883.0009) substitution. The mutations were identified by high-throughput targeted exome sequencing of 144 known genes responsible for inherited retinal diseases. Both mutations affected highly conserved residues and were not found in 300 controls. The Y461C mutation was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project (ESP6500) databases. R534Q was found in the dbSNP database (rs199910690, frequency not provided) and at a low frequency (0.0005) in the 1000 Genomes Project database; it was not present in the Exome Sequencing Project database. Functional studies of the variants were not performed.
For discussion of the arg534-to-gln (R534Q) mutation in the MKS1 gene that was found in compound heterozygous state in a patient with Bardet-Biedl syndrome-13 (BBS13; 615990) by Xing et al. (2014), see 609883.0008.
In a 44-year-old man (COR340) with Joubert syndrome-28 (JBTS28; 617121), Romani et al. (2014) identified a homozygous A-to-G transition in intron 16 of the MKS1 gene (c.1461-2A-G, NG_013032.1), predicted to result in a splice site alteration. Each unaffected parent was heterozygous for the mutation, which was not found in public databases. Functional studies of the variant and studies of patient cells were not performed.
In a 2-year-old child (COR413) with Joubert syndrome-28 (JBTS28; 617121), Romani et al. (2014) identified compound heterozygous mutations in the MKS1 gene: an in-frame 3-bp deletion (c.1085_1088delCCT, NG_013032.1), resulting in the deletion of conserved residue Ser362, and a G-to-T transversion in intron 16 (c.1558+1G-T; 609883.0012), predicted to result in a splice site mutation. Each unaffected parent was heterozygous for 1 of the mutations, which were not found in public databases. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the G-to-T transversion in intron 16 of the MKS1 gene (c.1558+1G-T, NG_013032.1) that was found in compound heterozygous state in a patient with Joubert syndrome-28 (JBTS28; 617121) by Romani et al. (2014), see 609883.0011.
Auber, B., Burfeind, P., Herold, S., Schoner, K., Simson, G., Rauskolb, R., Rehder, H. A disease causing deletion of 29 base pairs in intron 15 in the MKS1 gene is highly associated with the campomelic variant of the Meckel-Gruber syndrome. Clin. Genet. 72: 454-459, 2007. [PubMed: 17935508] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00880.x]
Bialas, N. J., Inglis, P. N., Li, C., Robinson, J. F., Parker, J. D. K., Healey, M. P., Davis, E. E., Inglis, C. D., Toivonen, T., Cottell, D. C., Blacque, O. E., Quarmby, L. M., Katsanis, N., Leroux, M. R. Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J. Cell Sci. 122: 611-624, 2009. [PubMed: 19208769] [Full Text: https://doi.org/10.1242/jcs.028621]
Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biol. 14: 61-72, 2012. [PubMed: 22179047] [Full Text: https://doi.org/10.1038/ncb2410]
Consugar, M. B., Kubly, V. J., Lager, D. J., Hommerding, C. J., Wong, W. C., Bakker, E., Gattone, V. H., II, Torres, V. E., Breuning, M. H., Harris, P. C. Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum. Genet. 121: 591-599, 2007. [PubMed: 17377820] [Full Text: https://doi.org/10.1007/s00439-007-0341-3]
Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A. The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum. Molec. Genet. 16: 173-186, 2007. [PubMed: 17185389] [Full Text: https://doi.org/10.1093/hmg/ddl459]
Gross, M. B. Personal Communication. Baltimore, Md. 2/19/2015.
Kyttala, M., Tallila, J., Salonen, R., Kopra, O., Kohlschmidt, N., Paavola-Sakki, P., Peltonen, L., Kestila, M. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nature Genet. 38: 155-157, 2006. [PubMed: 16415886] [Full Text: https://doi.org/10.1038/ng1714]
Leitch, C. C., Zaghloul, N. A., Davis, E. E., Stoetzel, C., Diaz-Font, A., Rix, S., Alfadhel, M., Lewis, R. A., Eyaid, W., Banin, E., Dollfus, H., Beales, P. L., Badano, J. L., Katsanis, N. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nature Genet. 40: 443-448, 2008. Note: Erratum: Nature Genet. 40: 927 only, 2008. [PubMed: 18327255] [Full Text: https://doi.org/10.1038/ng.97]
Romani, M., Micalizzi, A., Kraoua, I., Dotti, M. T., Cavallin, M., Sztriha, L., Ruta, R., Mancini, F., Mazza, T., Castellana, S., Hanene, B., Carlucio, M. A., Darra, F., Mate, A., Zimmermann, A., Gouider-Khouja, N., Valente, E. M. Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet J. Rare Dis. 9: 72, 2014. Note: Electronic Article. [PubMed: 24886560] [Full Text: https://doi.org/10.1186/1750-1172-9-72]
Salonen, R. The Meckel syndrome: clinicopathological findings in 67 patients. Am. J. Med. Genet. 18: 671-689, 1984. [PubMed: 6486167] [Full Text: https://doi.org/10.1002/ajmg.1320180414]
Tammachote, R., Hommerding, C. J., Sinders, R. M., Miller, C. A., Czarnecki, P. G., Leightner, A. C., Salisbury, J. L., Ward, C. J., Torres, V. E., Gattone, V. H., II, Harris, P. C. Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3. Hum. Molec. Genet. 18: 3311-3323, 2009. [PubMed: 19515853] [Full Text: https://doi.org/10.1093/hmg/ddp272]
Weatherbee, S. D., Niswander, L. A., Anderson, K. V. A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and hedgehog signaling. Hum. Molec. Genet. 18: 4565-4575, 2009. [PubMed: 19776033] [Full Text: https://doi.org/10.1093/hmg/ddp422]
Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230] [Full Text: https://doi.org/10.1083/jcb.201012116]
Xing, D.-J., Zhang, H.-X., Huang, N., Wu, K.-C., Huang, X.-F., Huang, F., Tong, Y., Pang, C.-P., Qu, J., Jin, Z.-B. Comprehensive molecular diagnosis of Bardet-Biedl syndrome by high-throughput targeted exome sequencing. PLoS One 9: e90599, 2014. Note: Electronic Article. [PubMed: 24608809] [Full Text: https://doi.org/10.1371/journal.pone.0090599]