Alternative titles; symbols
HGNC Approved Gene Symbol: MKKS
SNOMEDCT: 702407009;
Cytogenetic location: 20p12.2 Genomic coordinates (GRCh38) : 20:10,401,009-10,434,222 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.2 | Bardet-Biedl syndrome 6 | 605231 | Autosomal recessive | 3 |
| McKusick-Kaufman syndrome | 236700 | Autosomal recessive | 3 |
Stone et al. (2000) analyzed the approximately 450-kb critical region on chromosome 20p12 for McKusick-Kaufman syndrome (MKKS; 236700) by sample sequencing, which revealed the presence of several known genes and EST clusters. Candidate transcripts were evaluated by Northern blot analysis of adult and fetal tissues. They selected 1 transcript with widespread expression for analysis in a patient from an Amish pedigree and a sporadic, non-Amish case. The Old Order Amish patient was found to be homozygous for an allele that had 2 missense substitutions, and the non-Amish patient was compound heterozygous for a frameshift mutation predicting premature protein truncation and a distinct missense mutation. The MKKS transcript has a predicted open reading frame of 570 amino acids Northern blot analysis revealed broad expression of a 2.4-kb transcript in human adult and fetal tissues. The MKKS predicted protein showed amino acid similarity to the chaperonin family of proteins (see 118190), suggesting a role for protein processing in limb, cardiac, and reproductive system development. Its closest protein relative is the alpha subunit of the Thermoplasma acidophilum thermosome.
Stone et al. (2000) determined that the MKKS gene has 6 exons with a start codon in exon 3 and 2 alternative 5-prime terminal exons that are noncoding.
Crystal Structure
Stone et al. (2000) modeled the 3-dimensional structure of the MKKS protein using data from the x-ray crystal structure of the T. acidophilum group II chaperonin protein.
Using live cell imaging techniques, Hirayama et al. (2008) observed that MKKS was highly mobile and rapidly shuttled between the cytosol and centrosome. Several disease-associated mutations altered the degradation and/or solubility of the MKKS protein. The mutations T57A (604896.0010), C499S (604896.0013), and Y37C (604896.0003) caused both increased MKKS degradation and reduced solubility relative to wildtype MKKS, and the H84Y (604896.0001), whereas the A242S, R155L, and G345E mutations increased MKKS degradation only. Proteasome inhibition resulted in aggregation of the G345E mutant at the centrosome; however, the Y37C mutant was immobilized at the centrosome even in the absence of proteasome inhibition. The G345E and Y37C mutants were also highly polyubiquitinated, and immunoprecipitation analysis revealed that the rapidly degraded G345E mutant was recognized by components of the ubiquitin-proteasome protein degradation pathway, HSP70 (see HSPA1A; 140550), HSC70 (HSPA8; 600816), HSP90 (see HSPCA; 140571), and CHIP (STUB1; 607207). Knockdown of CHIP by RNA interference reduced the polyubiquitination and degradation of the G345E mutant protein. Hirayama et al. (2008) concluded that CHIP activity modulates the aggregation and stability of some MKKS mutant proteins.
Mice homozygous for the rd16 truncation mutation in the centrosomal protein Cep290 (610142) develop early-onset retinal degeneration. Rachel et al. (2012) found that Cep290 and Mkks localized to adjacent regions in ciliated sensory cells in mice. Yeast 2-hybrid and coimmunoprecipitation analyses showed that full-length human MKKS interacted with the C-terminal domain of human CEP290 corresponding to the region deleted in rd16 mice, as well as with full-length CEP290. Some Bardet-Biedl syndrome (BBS; see 605231)-associated MKKS mutants (e.g., G52D; 604896.0005) showed weak or nonexistent interaction with the CEP290 C-terminal domain in yeast 2-hybrid analysis.
Scott et al. (2017) used CRISPR/Cas9 to knockout Mkks in mouse medullary collecting duct cells and induced ciliation by serum starvation. They observed a reduced number of ciliated mutant cells compared with wildtype cells. Transfection of mutant cells with wildtype human MKKS or with the McKusick-Kaufman syndrome-associated MKKS(H84Y/A242S) allele rescued the ciliation defect. Using inhibitor studies in HEK293T cells, the authors showed that MKKS required active transport to overcome nuclear accumulation, as demonstrated by fluorescence microscopy and cell fractionation. Nuclear transport was disrupted in cells transfected with MKKS(H84Y/A242S), but not in cells transfected with wildtype MKKS or with the BBS-associated allele MKKS(Y37C). Using GFP-tagged MKKS protein, immunoprecipitation, and confocal microscopy, Scott et al. (2017) identified SMARCC1 (601732) as a predominantly cytoplasmic interacting partner of MKKS in zebrafish and HEK293T cells. Knockout of MKKS in HEK293T cells resulted in decreased SMARCC1 expression in cytoplasm. MKKS overexpression enhanced SMARCC1 cytoplasmic expression. Transfection with MKKS(H84Y/A242S) resulted in increased cytoplasmic retention of SMARCC1 compared with wildtype MKKS. Scott et al. (2017) proposed that MKKS has an important function in nuclear-cytoplasmic transport.
McKusick-Kaufman Syndrome
In an Amish patient with McKusick-Kaufman syndrome (MKKS; 236700), Stone et al. (2000) identified homozygosity for 2 missense substitutions in cis in the MKKS gene (604896.0001). In a non-Amish patient with MKKS, they identified compound heterozygous mutations in the MKKS gene: a frameshift mutation predicting premature protein termination (604896.0004) and a missense mutation (604896.0003).
Bardet-Biedl Syndrome
Slavotinek et al. (2000) and Katsanis et al. (2000) identified a sixth form of Bardet-Biedl syndrome (BBS6; 605231), which is due to mutations in the MKKS gene (see, e.g., 604896.0007). Bardet-Biedl syndrome is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism, and renal malformations, with secondary features that include diabetes mellitus, endocrinologic dysfunction, and behavioral abnormalities. Katsanis et al. (2000) performed a genome screen in BBS families from Newfoundland in which linkage to known BBS loci had been excluded. Fine mapping reduced the critical interval to a region including the MKKS gene. Given the mapping position and the clinical similarity between McKusick-Kaufman syndrome and Bardet-Biedl syndrome, they screened the MKKS gene and identified mutations in 5 Newfoundland and 2 European-American BBS pedigrees. Most were frameshift mutations, predicted to result in a nonfunctional protein. The data suggested that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, leads to the clinical manifestations of BBS.
Slavotinek et al. (2000) ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa, obesity, and polydactyly. The probands were from families unsuitable for linkage because of family size. They found MKKS mutations in 4 typical BBS probands. Three of the probands were from Newfoundland and had been included in the study of Katsanis et al. (2000). Slavotinek et al. (2000) likewise suggested that the clinical features of BBS may be caused by the inability of the MKKS putative chaperonin to maintain protein integrity in the retina, brain, pancreas, and other organs. The results suggested that genes encoding chaperonins and their substrates are candidates for other BBS loci, retinitis pigmentosa, diabetes, obesity, and mental retardation.
Beales et al. (2001) found mutations in MKKS in only 4 to 11% of unselected BBS patients. Slavotinek et al. (2002) hypothesized that an analysis of patients with atypical BBS and MKKS (group I; 15 probands) and patients with BBS who had linkage results inconsistent with linkage to other BBS loci (group II; 12 probands) could increase the MKKS mutation yield. Two mutant alleles in the MKKS gene were identified in only 2 families in group II. Single (heterozygous) sequence variations were found in 3 group I families and in 2 group II families. Combining these results with previously published data showed that only 1 mutant allele was detected in nearly half of all patients screened, suggesting that unusual mutational mechanisms or patterns of inheritance may have been involved. However, sequencing of the BBS2 gene (606151) in these patients did not provide any evidence of digenic triallelic inheritance. The frequency of detected mutations in MKKS in group II patients was 24%, i.e., 6 times higher than the published rate for unselected BBS patients, suggesting that small-scale linkage analyses may be useful in suitable families.
Karmous-Benailly et al. (2005) sequenced the BBS6 gene and others of the 8 genes (BBS1-BBS8) that have been identified as mutant in BBS. They speculated that because of the clinical overlap in the features of BBS observed at birth (polydactyly, kidney anomalies, hepatic fibrosis, and genital and heart malformations) with those of Meckel syndrome (249000), some fetuses diagnosed as having Meckel or 'Meckel-like' syndrome (see 208540) might have mutations in a BBS gene. Indeed, they found a recessive mutation in the BBS2 gene in 3 such fetuses, 2 in BBS4 (600374), and 1 in BBS6. They also found a heterozygous BBS6 mutation in 3 additional cases.
Badano et al. (2003) presented 3 families with 2 mutations in either the BBS1 gene or the BBS2 gene, in which some, but not all, patients carried a third mutation in the BBS1, BBS2, or BBS6 genes. In each example, the presence of 3 mutant alleles correlated with a more severe phenotype. The introduction in mammalian cells of 1 of the mutations in the BBS6 gene (604896.0014) caused a dramatic mislocalization of the protein compared with the wildtype. Badano et al. (2003) suggested that 3 mutant alleles are not always necessary for disease manifestation, but might potentiate a phenotype that is caused by 2 mutations at an independent locus, thus introducing an additional layer of complexity on the genetic modeling of oligogenicity.
In a population-based study including 93 BBS patients from 74 families of various ethnicities, Billingsley et al. (2010) determined that the chaperonin-like BBS6, BBS10 (610148), and BBS12 (610683) genes are a major contributor to the disorder. Biallelic mutations in these 3 genes were found in 36.5% of the families: 4 patients had mutations in BBS6, 19 had mutations in BBS10, and 10 had mutations in BBS12. Overall, 26 (68%) of 38 mutations were novel. Six patients had mutations present in more than 1 chaperonin-like BBS gene, and 1 patient with a very severe phenotype had 4 mutations in BBS10. The phenotypes observed were beyond the classic BBS phenotype and overlapped with characteristics of MKKS (236700), including congenital heart defect, vaginal atresia, hydrometrocolpos, and cryptorchidism, and with Alstrom syndrome (203800), including diabetes, hearing loss, liver abnormalities, endocrine anomalies, and cardiomyopathy.
Associations Pending Confirmation
To investigate whether variation in the MKKS gene contributes to common and probably polygenic forms of obesity, Andersen et al. (2005) performed mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. They identified 5 variants, including the rare ala242-to-ser mutation (see 604896.0001) in 2 families, where it showed partial cosegregation with obesity. Other variants failed to show an association. The authors concluded that it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.
For discussion of a possible association between variation in the MKKS gene and the metabolic syndrome, see AOMS1 (605552).
Fath et al. (2005) developed an Mkks -/- mouse model in which affected animals demonstrated retinal degeneration, failure of spermatozoa flagella formation, elevated blood pressure, olfactory deficits, and social dominance, but no polydactyly nor vaginal abnormalities. The phenotype of the Mkks -/- mice closely resembled the phenotype of other mouse models of Bardet-Biedl syndrome (Bbs2 -/- and Bbs4 -/-). Fath et al. (2005) suggested that the complete absence of the MKKS gene leads to BBS while the McKusick-Kaufman phenotype is likely to be due to specific mutations.
Stoetzel et al. (2007) suppressed BBS6, BBS10, and BBS12 (610683) in zebrafish and observed gastrulation-movement defects characteristic of other BBS morphants. Suppression of each of these chaperonin-like molecules yielded highly overlapping phenotypes, but simultaneous suppression of these 3 genes, which comprise a subfamily, grossly exaggerated the penetrance and expressivity of these phenotypes. Stoetzel et al. (2007) suggested that this effect might underlie either some partial functional redundancy within the subfamily or might reflect the progressive loss of pericentriolar function.
Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the met390-to-arg (M390R; 209901.0001) mutation in Bbs1 (209901), Shah et al. (2008) showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness.
Rahmouni et al. (2008) studied Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice and found that obesity was associated with hyperleptinemia (164160) and resistance to the anorectic and weight-reducing effects of leptin. Although all 3 of the BBS mouse models were similarly resistant to the metabolic actions of leptin, only Bbs4 -/- and Bbs6 -/- mice remained responsive to the effects of leptin on renal sympathetic nerve activity and arterial pressure and developed hypertension. The authors also found that BBS mice had decreased hypothalamic expression of proopiomelanocortin (POMC; 176830), and suggested that BBS genes play an important role in maintaining leptin sensitivity in POMC neurons.
Mice homozygous for the rd16 truncation mutation in Cep290 develop early-onset retinal degeneration. Rachel et al. (2012) demonstrated that the rd16 mutation removes a domain of Cep290 that interacts with Mkks (see GENE FUNCTION). They found that haploinsufficiency of Mkks at least partly rescued ciliary pathology in some mice homozygous for the rd16 mutation. Likewise, haploinsufficiency of Cep290 partly rescued ciliary pathology in Mkks -/- mice. In contrast, haploinsufficiency of both proteins in zebrafish exacerbated ciliary defects found in single-mutant animals.
Scott et al. (2017) knocked down Bbs6 in zebrafish using 2 independent morpholino oligonucleotides and observed Kupffer vesicle (KV) cilia defects and delays in retrograde cellular transport, as seen with knockdown of other BBS genes. Fluorescent microscopy demonstrated a significant reduction of KV cilia length, but transfection with wildtype human MKKS or with the human McKusick-Kaufman syndrome-associated allele MKKS(H84Y/A242S) allowed for ciliogenesis and cilia maintenance.
In an Old Order Amish patient with McKusick-Kaufman syndrome (MKKS; 236700), Stone et al. (2000) identified homozygosity for 2 mutations on the same allele in the MKKS gene. One was a 1137C-T transition, resulting in a his84-to-tyr (H84Y) substitution, and the other resulted in an ala242-to-ser (A242S) substitution. This allele, with both alterations, was found in 1 of 100 Amish 'control' chromosomes, which suggests a carrier frequency of approximately 2%, similar to the estimated carrier frequency calculated using the incidence of this disorder among the Amish. Neither Amish substitution was found in an additional 100 non-Amish control chromosomes. The H84Y mutation was predicted to interfere with ATP hydrolysis, which in other chaperonins leads to substantially reduced function. Three individuals homozygous for the affected chromosome had a normal phenotype, consistent with the incomplete penetrance of the MKKS phenotype.
In a follow-up study of the Amish family reported by Stone et al. (2000) in which the unaffected mother was homozygous for the H84Y and A242S mutations, Nakane and Biesecker (2005) excluded triallelic inheritance for multiple BBS genes (see, e.g., BBS1, 209901) as an explanation for the incomplete penetrance.
In a sporadic non-Amish case of McKusick-Kaufman syndrome (MKKS; 236700), Stone et al. (2000) identified an A-to-G transition at nucleotide 997 of the MKKS gene, resulting in a tyrosine-to-cysteine substitution at codon 37 (Y37C). This mutation was not identified in over 200 chromosomes from a non-Amish control group. The patient was a compound heterozygote for a frameshift mutation (604896.0004).
The same Y37C mutation was found in homozygous state in a pedigree with Bardet-Biedl syndrome-6 (BBS6; 605231) (Katsanis et al., 2000).
Katsanis et al. (2001) reported an individual who was homozygous for the Y37C mutation and carried a third mutation, which they stated was an asn70-to-ser (N70S) substitution in the BBS2 gene; however, gnomAD (v2.1.1) lists serine as the reference allele.
In a sporadic non-Amish case of McKusick-Kaufman syndrome (MKKS; 236700), Stone et al. (2000) identified a 2-bp deletion at nucleotide 2111 and 2112 of the MKKS gene, resulting in a frameshift leading to premature termination. This mutation was maternally inherited.
In a patient with Bardet-Biedl syndrome-6 (BBS6; 605231), a 13-year-old Hispanic girl with severe retinitis pigmentosa, postaxial polydactyly, mental retardation, and obesity, Slavotinek et al. (2000) found compound heterozygosity for a missense (1042G-A, gly52 to asp; G52D) and a nonsense (1679T-A, tyr264 to ter; Y264X) mutation in exon 3 of the MKKS gene.
Rachel et al. (2012) showed that MKKS with the G52D mutation was unable to interact with the C-terminal domain of the centrosomal protein CEP290 (610142).
For discussion of the tyr264-to-ter (T264X) mutation in the MKKS gene that was found in compound heterozygous state in a patient with Bardet-Biedl syndrome-6 (BBS6; 605231) by Slavotinek et al. (2000), see 604896.0005.
Katsanis et al. (2000) found that all affected individuals from 2 Newfoundland pedigrees (families NF-B3 and NF-B4) with Bardet-Biedl syndrome-6 (BBS6; 605231) were homozygous for deletion of 280T of the MKKS gene, which resulted in a frameshift after amino acid phenylalanine-94, terminating the protein at amino acid 103. They found the same alteration in compound heterozygous state in 2 other patients (see 604896.0008 and 604896.0009), and it segregated with a haplotype-inferred prediction of a common ancestral chromosome in the 4 pedigrees.
Slavotinek et al. (2000) had independently studied the same Newfoundland families (their families 3 and 4) and identified a homozygous 1167delT mutation in each. In an erratum, the authors stated that their numbering differed from that of Katsanis et al. (2000) because they chose the 5-prime end of the sequence (GenBank AF221993) as '1,' whereas Katsanis et al. (2000) chose the A of the putative ATG. Moreover, they stated that according to nomenclature convention, the numbering should have been 1168delT and 281delT, respectively.
In a Newfoundland patient with Bardet-Biedl syndrome-6 (BBS6; 605231), Katsanis et al. (2000) found compound heterozygosity for 2 mutations in the MKKS gene: 280delT (604896.0007) and a missense mutation, leu277 to pro (L277P). The same patient was reported by Moore et al. (2005) as having been clinically diagnosed with Laurence-Moon syndrome (245800). Moore et al. (2005) considered their identification of mutations in the MKKS gene in a patient with Laurence-Moon syndrome as supporting the notion that Bardet-Biedl syndrome and Laurence-Moon syndrome are the same disorder.
In 2 affected members of a Newfoundland family segregating Bardet-Biedl syndrome-6 (BBS6; 605231), Katsanis et al. (2000) detected homozygosity for a complex 429delCT/433delAG allele of the MKKS gene that resulted in a frameshift of the termination of the protein at amino acid 157. Cloning and sequencing of the PCR product from 1 subject indicated that both deletions were on the same strand, suggesting that this mutation arose through a complex mechanism.
In an independent study of the same Newfoundland family (their family 2) segregating BBS6, Slavotinek et al. (2000) identified homozygosity for 2 deletions in the MKKS gene, which they designated 1316delC and 1324-1326delGTA, in exon 3 of the MKKS gene, predicting a frameshift. In an erratum, Slavotinek et al. (2000) attributed the discrepancy in the naming of this mutation to ambiguity in the nomenclature system and the absence of biologic data that could resolve the discrepancy. The parents in this family were related. The proband and her affected brother had retinitis pigmentosa, postaxial polydactyly, mild mental retardation, morbid obesity, lobulated kidneys with prominent calyces, and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister had similar phenotypic features (retinitis pigmentosa with blindness by age 13, BMI greater than 45, abnormal glucose tolerance test, an IQ of 64, vaginal atresia, and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions.
Katsanis et al. (2000) identified 2 affected members of another Newfoundland family with BBS6 who were compound heterozygous for this complex mutation and another frameshift mutation (604896.0007).
In a pedigree with Bardet-Biedl syndrome-6 (BBS6; 605231), Katsanis et al. (2000) found that 1 MKKS allele carried a thr57-to-ala (T57A) mutation.
Rachel et al. (2012) showed that MKKS with the T57A mutation exhibited reduced interaction with the C-terminal domain of the centrosomal protein CEP290 (610142).
In a patient carrying 2 different termination codons in the BBS2 gene (606151.0003, 606151.0004), Katsanis et al. (2001) identified a nonsense mutation in the BBS6 gene, a glutamine-to-termination substitution at codon 147.
In a patient who was compound heterozygous for 2 nonsense mutations in the BBS2 gene, a leu168 frameshift, leading to a termination codon at residue 170 (606151.0014), and an arg216-to-ter mutation (606151.0016), Katsanis et al. (2001) identified a third mutation in the MKKS gene, a cysteine-to-serine substitution at codon 499.
Rachel et al. (2012) showed that MKKS with the C499S mutation exhibited reduced interaction with the C-terminal domain of the centrosomal protein CEP290 (610142).
In 1 of 2 sisters with BBS1 (209900), Badano et al. (2003) identified a 973A-C transversion in exon 3 of the MKKS gene, resulting in a thr325-to-pro (T325P) substitution which altered the 3-dimensional protein structure. Both sisters were compound heterozygous for mutations in the BBS1 gene: met390-to-arg (M390R; 209901.0001) and a 1-bp deletion (1650delC; 209901.0008). The sister with the T325P mutation was more severely affected than the sister without the mutation.
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