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MKKS
MKKS centrosomal shuttling protein
The MKKS gene, also known as BBS6, provides instructions for a protein essential for early development, including the formation of limbs, heart, and reproductive system, and is involved in cilia function. The MKKS gene encodes a protein that appears to be a chaperonin, assisting in the proper folding of other proteins.
MKKS is located on the short (p) arm of chromosome 20, at band 20p12.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MKKS gene (also referred to as BBS6) contains instructions for producing a protein that is fundamental for several aspects of early human development. These include the proper formation of the limbs, heart, and reproductive system. The protein's structure suggests it may function as a chaperonin, a type of protein that helps other proteins fold correctly to achieve their functional shapes.
What the gene does
The protein produced from the MKKS gene is believed to act as a chaperonin, facilitating the correct three-dimensional folding of other proteins within the cell. This proper folding is crucial for protein function. The MKKS protein interacts with other proteins to form a chaperonin complex, which serves as a structural scaffold for the assembly of another important molecular complex called the BBSome. The BBSome plays a key role in transporting materials that are necessary for the function of cilia, which are small, finger-like projections on cell surfaces involved in transmitting signals. Additionally, research suggests the MKKS protein might directly transport molecules, such as the SMARCC1 protein, from the cytoplasm into the cell's nucleus, where SMARCC1 helps regulate gene activity.
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Chromosome location
The MKKS gene is situated on the short arm of chromosome 20 at position 12.2, specifically designated as 20p12.2. This genomic location dictates where the genetic information for the MKKS protein is stored within the human genome.
Protein structure
The MKKS protein is composed of 570 amino acids. Its structural organisation includes a key functional region known as the Substrate-binding apical domain, spanning amino acids 198-370. This domain is likely critical for the protein's proposed chaperonin activity, enabling it to bind to and facilitate the folding of other proteins.
Key variants
Genetic variations within the MKKS gene can lead to altered protein function, impacting its role in early development and cilia maintenance. These changes can range from single nucleotide substitutions to larger deletions or insertions, and their specific effects depend on the nature and location of the variant within the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1171C>T | p.Gln391Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome |
c.1186G>T | p.Val396Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome |
c.1310_1311del | p.Glu437fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome |
c.1368del | p.Val457fs | Pathogenic/Likely pathogenic | ★★☆☆ | McKusick-Kaufman syndrome |
c.1410_1413del | p.Thr470_Asp471insTer | Pathogenic/Likely pathogenic | ★★☆☆ | McKusick-Kaufman syndrome |
c.1434G>A | p.Trp478Ter | Pathogenic/Likely pathogenic | ★★☆☆ | McKusick-Kaufman syndrome |
c.257C>A | p.Ser86Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome 6 |
c.2T>G | p.Met1Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome |
c.885dup | p.Val296fs | Pathogenic | ★★☆☆ | Bardet-Biedl syndrome |
c.966del | p.Glu322fs | Pathogenic/Likely pathogenic | ★★☆☆ | McKusick-Kaufman syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the MKKS gene are associated with inherited conditions primarily affecting development and cellular function. These conditions often present with a range of symptoms impacting multiple organ systems, underscoring the gene's broad importance in human biology. Specific conditions linked to MKKS variants include Bardet-Biedl syndrome, and a few variants have been identified in individuals with McKusick-Kaufman syndrome.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MKKS variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The MKKS gene is included in several NHS England Genomic Medicine Service approved panels. These panels cover a range of conditions, including Bardet Biedl syndrome (R107), Foetal anomalies (R21), Ophthalmological ciliopathies, Rare multisystem ciliopathy disorders, Renal ciliopathies, Retinal disorders (R32), and Severe early-onset obesity (R149). It is also part of panels for DDG2P, Intellectual disability, Limb disorders, and Skeletal dysplasia.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the MKKS gene?
The MKKS gene provides instructions for a protein that likely acts as a chaperonin, helping other proteins fold correctly. It is also crucial for assembling the BBSome, which supports the function of cilia, and may transport molecules within the cell.
Which conditions are associated with variants in the MKKS gene?
Variants in the MKKS gene are primarily associated with Bardet-Biedl syndrome. Some variants have also been linked to McKusick-Kaufman syndrome.
What is a chaperonin?
A chaperonin is a type of protein that assists in the proper folding of other proteins into their correct three-dimensional shapes. This correct folding is essential for proteins to function effectively within the cell.
References
- Seo S, Baye LM, Schulz NP. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proceedings of the National Academy of Sciences of the United States of America. 2010. PMID: 20080638
- Hirayama S, Yamazaki Y, Kitamura A. MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination. Molecular biology of the cell. 2008. PMID: 18094050
- Kim JC, Ou YY, Badano JL. MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. Journal of cell science. 2005. PMID: 15731008
- Slavotinek AM, Searby C, Al-Gazali L. Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients. Human genetics. 2002. PMID: 12107442
- Slavotinek AM, Biesecker LG. Unfolding the role of chaperones and chaperonins in human disease. Trends in genetics : TIG. 2001. PMID: 11525836
- Stone DL, Slavotinek A, Bouffard GG. Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nature genetics. 2000. PMID: 10802661
- Slavotinek AM, Stone EM, Mykytyn K. Mutations in MKKS cause Bardet-Biedl syndrome. Nature genetics. 2000. PMID: 10973238
- Katsanis N, Beales PL, Woods MO. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nature genetics. 2000. PMID: 10973251
- Adam MP, Bick S, Mirzaa GM. McKusick-Kaufman Syndrome. 1993. PMID: 20301675