MKKS

protein-coding

MKKS centrosomal shuttling protein, the group of Chaperonins

Gene summary

This gene encodes a protein which shares sequence similarity with other members of the type II chaperonin family. The encoded protein is a centrosome-shuttling protein and plays an important role in cytokinesis. This protein also interacts with other type II chaperonin members to form a complex known as the BBSome, which involves ciliary membrane biogenesis. This protein is encoded by a downstream open reading frame (dORF). Several upstream open reading frames (uORFs) have been identified, which repress the translation of the dORF, and two of which can encode small mitochondrial membrane proteins. Mutations in this gene have been observed in patients with Bardet-Biedl syndrome type 6, also known as McKusick-Kaufman syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2023]

Previous symbols:

BBS6

MANE transcript

NM_170784.3

Inheritance

ClinVar variants

P:144U:281B:217

Top phenotype

Bardet-Biedl syndrome 6; McKusick-Kaufman syndrome

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr20:10,401,009-10,434,222

External References & Databases

Ensembl (ENSG00000125863)

Transcript & Mutation Effects

hg38 • Region Span ~33.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Natera

McKusick-Kaufman syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009367

Submitter: Labcorp Genetics (formerly Invitae)

ciliopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: PanelApp Australia

MKKS-related ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1040050

Submitter: ClinGen

*MKKS* was first reported in relation to autosomal recessive Bardet-Biedl syndrome (BBS) in 2000 by two groups, Slavotinek et al. (PMID: 10973238) and Katsanis et al. (PMID: 10973251). BBS is a rare genetically heterogeneous ciliopathy, characterized by rod-cone dystrophy, polydactyly, obesity, genital anomalies, renal anomalies, and intellectual disabilities. *MKKS* variants have also been reported in relation to cases diagnosed as McKusick-Kaufman syndrome (PMID: 10802661). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *MKKS* loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 6 (MIM# 605231) or McKusick-Kaufman syndrome (MIM# 236700), while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *MKKS* variants have been lumped into a single disease entity, referred to as MKKS-related ciliopathy. This curation includes twelve variants (five missense, three nonsense and four frameshift) that have been reported in thirteen probands in eight publications (PMIDs: 10973238, 10973251, 12107442, 20472660, 15770229, 20177705, 28761321 and 30718709). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental data showing that *MKKS* is expressed in tissues affected by BBS (PMID: 10973238 ). This gene-disease association is also supported by biochemical evidence that the MKKS protein shares a function with the products of the *BBS10* and *BBS12* genes to mediate the assembly of the BBSome, a complex that performs vesicle transport to primary cilia and contributes to adipocyte differentiation. Through yeast two hybrid and coimmunoprecipitatin assays, Rachel et al. 2012 show that MKKS physically interacts with CEP290, a critical protein in ciliary biogenises and function, and that MKKS variants found in human BBS patients disrupt this protein-protein interaction (PMID: 22446187). Finally, multiple *Mkks*-knockout mouse models show that mice without a functional copy of *Mkks* display severe retinal degeneration compared to wild-type mice (PMIDs: 30901771 and 15772095). In summary, *MKKS* is definitively associated with autosomal recessive MKKS-related ciliopathy. 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 Retina GCEP on May 2nd, 2024 (SOP Version 10).

McKusick-Kaufman syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009367

Submitter: G2P

McKusick-Kaufman syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009367

Submitter: Orphanet

Bardet-Biedl syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Bardet-Biedl syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011523

Submitter: Genomics England PanelApp

Bardet-Biedl syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011523

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Bardet-Biedl syndrome 6; McKusick-Kaufman syndromeAR

Manifestation: Cardiovascular; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Endocrine

Rationale: McKusick-Kaufman syndrome can involve congenital cardiac anomalies, and awareness may allow early management; In Bardet-Biedl syndrome, medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Comments: Variants may modify severity of BBS and related disorders due to variants in other BBS-associated genes

Refs: 14172277; 5694533; 5545396; 7262101; 7246610; 2681663; 2564737; 8209897; 10465109; 10973251; 11102925; 10802661; 11567139; 12837689; 15637713; 16104012; 20301537; 20301675; 36356613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MKKS variants in ClinVar

18 Conditions Cataloged

McKusick-Kaufman syndromeTotal: 504

Bardet-Biedl syndromeTotal: 462

MKKS-related disorderTotal: 260

Bardet-Biedl syndrome 6Total: 194

not providedTotal: 94

Inborn genetic diseasesTotal: 75

not specifiedTotal: 59

Retinal dystrophyTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_170784.3. 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				198 clinvar		198
missense	3 clinvar	23 clinvar	276 clinvar	18 clinvar	1 clinvar	321
nonsense	14 clinvar	25 clinvar	2 clinvar			41
start loss	2 clinvar	2 clinvar				4
frameshift	29 clinvar	40 clinvar	2 clinvar			71
splice donor/acceptor (+/-2bp)	4 clinvar	2 clinvar	1 clinvar			7
Total	52	92	281	216	1	642

Highest pathogenic variant AF is 0.00016428668

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_170784.3	RefSeq	NP_740754.1	4	MANE Select
ENST00000347364.7	Ensembl	ENSP00000246062.4	4	MANE Select
NM_018848.3	RefSeq	NP_061336.1	4	Standard
ENST00000399054.6	Ensembl	ENSP00000382008.2	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mkks	Danio rerio	Structure: pharyngeal arch 3-7 Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

mkks

Danio rerio

Structure: pharyngeal arch 3-7

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrated Lung Cancer Pathway
BBSome-mediated cargo-targeting to cilium
Cargo trafficking to the periciliary membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

heart looping
protein folding
spermatid development
determination of left/right symmetry
heart development

Molecular Function

RNA polymerase II repressing transcription factor binding
protein binding
ATP binding
unfolded protein binding

Cellular Component

nucleus
cytoplasm
centrosome
cytosol
motile cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347364
Coding exons: 4
Length: 33214
Individuals with no LoFs: 125681
Homozygous LoFs: 0
Heterozygous LoFs: 65
Defined: 125746
p: 0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0520	288	286	1.01	0.0000138	3687
Missense (PolyPhen)		60	78.614	0.76322		1065
Synonymous	-1.51	129	109	1.18	0.00000537	1163
Loss of Function	0.648	15	18.0	0.835	8.32e-7	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00056	0.00056	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis (PubMed:20080638). Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638). May play a role in protein processing in limb, cardiac and reproductive system development. May play a role in cytokinesis (PubMed:28753627). {ECO:0000269|PubMed:20080638, ECO:0000269|PubMed:28753627}.;
Disease: DISEASE: McKusick-Kaufman syndrome (MKKS) [MIM:236700]: Autosomal recessive developmental disorder. It is characterized by hydrometrocolpos, postaxial polydactyly and congenital heart defects. {ECO:0000269|PubMed:10802661, ECO:0000269|PubMed:28753627}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bardet-Biedl syndrome 6 (BBS6) [MIM:605231]: 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:10973238, ECO:0000269|PubMed:10973251, ECO:0000269|PubMed:11179009, ECO:0000269|PubMed:11567139, ECO:0000269|PubMed:12107442, ECO:0000269|PubMed:12677556, ECO:0000269|PubMed:12920096, ECO:0000269|PubMed:15666242, ECO:0000269|PubMed:15731008, ECO:0000269|PubMed:15770229, ECO:0000269|PubMed:18094050, ECO:0000269|PubMed:20080638, ECO:0000269|PubMed:21344540, ECO:0000269|PubMed:22152675, ECO:0000269|PubMed:26900326, ECO:0000269|PubMed:28753627, ECO:0000269|PubMed:28761321}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.306

Intolerance Scores

LoFtool: 0.265
RVIS EVS: 0.35
RVIS percentile EVS: 74.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.507

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium