DiagnosisClinical DiagnosisFormal clinical diagnostic criteria for McKusick-Kaufman syndrome (MKS) have not been published.The diagnosis of MKS in females is based on the triad of hydrometrocolpos (HMC), postaxial polydactyly (PAP), and congenital heart disease (CHD) without manifestations of overlapping syndromes such as Bardet-Biedl syndrome (BBS). The diagnosis of MKS in males is based on genital malformations (most commonly hypospadias, cryptorchidism, and chordee), PAP, and CHD. Hydrometrocolpos (HMC) in infants is dilatation of the vagina and uterus caused by the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by: Failure of the distal third of the vagina to develop (vaginal agenesis) A transverse vaginal membrane Imperforate hymen; however, in the child with this finding reported by El-Messidi & Fleming [2006], it was too early to know if the actual diagnosis was MKS or BBS. HMC often presents at birth as a large, cystic abdominal mass arising out of the pelvis, which can be sufficiently large to be clinically obvious and is verified using an ultrasound scan. The mass can be large enough to cause intestinal obstruction, urinary outflow obstruction leading to dilatation of the ureter (hydroureter) and kidneys (hydronephrosis), inferior vena caval obstruction, and/or elevation of the diaphragm resulting in breathing difficulties.Postaxial polydactyly (PAP) is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot. The additional digit can be fully formed or can be a rudimentary skin tag (often called a "minimus"). If clinical examination is insufficient, radiographs may be used to determine whether the polydactyly is postaxial or mesoaxial (also known as insertional) (i.e., the presence of an extra digit or digits anywhere between the thumb and fifth finger). Mesoaxial polydactyly is much less common than postaxial polydactyly. Congenital heart disease (CHD). Cardiac malformations that have been described at least once in individuals with MKS are atrioventricularis (AV) communis with a left-sided superior vena cava, atrial septal defect, ventricular septal defect, AV canal, small aorta and hypoplastic left ventricle, tetralogy of Fallot, and patent ductus arteriosus [Slavotinek & Biesecker 2000]. Because of the limited number of individuals with MKS and cardiac malformations, the relative incidences are unknown. Note: (1) Hydrometrocolpos and PAP in a non-Amish female without evidence of overlapping syndromes (see Differential Diagnosis) are sufficient for a clinical diagnosis of MKS [Slavotinek & Biesecker 2000]. (2) Because HMC and PAP can also be found in female infants with Bardet-Biedl syndrome (BBS), the diagnosis of MKS in a female with HMC and PAP must be delayed until at least age five years and requires absence of features of BBS (e.g., rod-cone dystrophy, developmental delay or intellectual disability, obesity, abnormalities of renal structure or function) [David et al 1999, Slavotinek & Biesecker 2000]. (3) Males with one or more features of the MKS triad should have at least one affected female relative to establish the clinical diagnosis of MKS. (4) Other physical findings in addition to the characteristic phenotypic triad associated with MKS are listed in Table 2. Although these features are nonspecific and have not been used to establish the diagnosis of MKS, the presence of renal anomalies may also prove useful in establishing the diagnosis of MKS.Molecular Genetic TestingGene. MKKS is the only gene currently known to be associated with McKusick-Kaufman syndrome (MKS). Other loci. Although genetic heterogeneity has not been demonstrated for the MKS phenotype and linkage to alternative loci or mutations in other Bardet-Biedel syndrome (BBS)-related genes (see Allelic Disorders) have not been reported [Katsanis et al 2000, Mykytyn et al 2001, Nishimura et al 2001, Mykytyn et al 2002, Ansley et al 2003, Li et al 2004], genetic heterogeneity remains a possibility. Clinical testing Sequence analysis. Mutations in MKKS have been found to date in the following: Individuals with MKS within the Amish population are all homozygous for the mutations p.His84Tyr or p.Ala242Ser [Stone et al 2000]. The frequency of the individual mutant alleles is unknown.
Note: (1) Both mutations (p.His84Tyr and p.Ala242Ser) were present in cis configuration on one chromosome from an apparently normal, "unrelated" Amish individual. This implies that they can be inherited together on the same allele without causing disease. (2) The phenotypic effects of both mutations in trans configuration are unknown, as this has not been observed. (3) Haplotype analysis could be considered as a means to distinguish between cis configuration and trans configuration in a symptomatic individual who has both mutations. One other non-Amish female with HMC and PAP, who was an infant at the time of her molecular genetic studies, was found to be compound heterozygous for p.Tyr37Cys and c.1215_1216delGG [Stone et al 2000]. It is not known if this child developed any of the age-dependent manifestations of BBS at an older age. Table 1. Summary of Molecular Genetic Testing Used in McKusick-Kaufman SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityMKKSSequence analysisSequence variants 2Up to 100% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations3. Mutations in MKKS were detected in the Amish pedigree with MKS, the only family definitely known to have this phenotype. Thus, the mutation detection frequency is unknown.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. Molecular genetic testing of MKKS is indicated for individuals with an MKS phenotype older than age five years in whom other clinical features of BBS have been excluded. However, if MKKS molecular genetic testing does not identify two disease-causing mutations, testing of other BBS-related genes should be considered given possible genetic heterogeneity of the MKS phenotype.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersBardet-Biedl syndrome (BBS) (see Differential Diagnosis). A substantial and prognostically significant clinical overlap between MKS and BBS has been noted [David et al 1999, Slavotinek & Biesecker 2000]. The close relationship between BBS and MKS has been further complicated by the demonstration of disease-causing sequence alterations in MKKS in both MKS and in an estimated 4%-6% of unselected individuals with BBS [Beales et al 2001, Hichri et al 2005, Moore et al 2005]. It therefore becomes pertinent to consider whether MKS should continue to remain a separate entity or henceforth be considered as belonging to the wider phenotypic spectrum that includes BBS. Of note, rare features associated with MKKS mutations and a BBS phenotype (not an MKS phenotype) include phimosis, urethral strictures, posterior urethral valves, and hypoplasia of the labia minora [Moore et al 2005]. Note: Sequencing of MKKS in individuals with BBS and phenotypic features found in MKS (such as HMC) does not increase the mutation detection rate in MKKS compared to other genes causing BBS [Slavotinek et al 2002].Although five variants in MKKS (p.Pro39Pro (NP_740754.1), p.Ile178Ile, p.Ala242Ser, p.Arg517Cys, p.Gly532Val (NP_061336.1) were identified in a cohort of 744 Danish men with juvenile-onset obesity, Andersen et al [2005] concluded that it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity. More recently, four tag single-nucleotide polymorphisms (SNPs), i.e., representative SNPs in a region of the genome with high linkage disequilibrium in MKKS (rs2294901, rs221667, rs6133922 and rs6077785), were found to be associated with metabolic syndrome in Japanese individuals, even after correcting for confounding factors of age and gender [Hotta et al 2009].}

Natural HistoryThe Amish form of McKusick-Kaufman syndrome (MKS) (HMC and PAP without age-dependent features of BBS) can be considered to be clinically and prognostically distinct from the BBS phenotype. In the Amish population, variable expressivity has been described: 70% of affected females have HMC, 60% of affected individuals of both sexes have PAP, and 15% of affected individuals of both sexes have CHD [Stone et al 1998, Slavotinek & Biesecker 2000]. Of note, many individuals with HMC and PAP diagnosed as having MKS were reported at an age too young to observe the age-dependent features of BBS [David et al 1999, Slavotinek & Biesecker 2000]. The true incidence of physical findings associated with the MKS phenotype is therefore unknown. Table 2 shows the most common associated features in 49 individuals with the MKS phenotype [Slavotinek & Biesecker 2000]; 75% were diagnosed at birth and 98% by age six months. Table 2. Phenotypic Features of Individuals with MKSView in own windowFindingNumber of Individuals Percent of IndividualsGenitourinary malformationsHMC42/4495%Vaginal agenesis26/4459%Urogenital sinus16/4436%Ectopic urethra8/4418%No urethral opening 6/4414%No vaginal opening4/449%Genitourinary tract fistulae 6/4414%PAP - Limbs affectedHands only12/42 29%Feet only6/42 14%Hands and feet ¹ 11/42 26%Four-limb polydactyly ¹ 11/42 26%Other digital anomaliesSyndactyly12/4924%Metacarpal/tarsal anomalies8/4916%Postaxial minimus 6/4912%Brachydactyly3/496%Absent phalanges2/494%Interstitial polydactyly0/480%Heptadactyly2/484%Renal anomaliesHydronephrosis31/4963%Hydroureter12/4924%Renal cysts2/494%Calyceal dilatation7/4914%Renal atrophy/hypoplasia ² 2/494%Corticomedullary dysplasia ³ 3/466%Nonfunctioning kidney 2/494%GI malformationsImperforate anus 4/498%Anal atresia 1/492%Hirschsprung disease6/4912%Anteriorly placed anus2/494%From Slavotinek & Biesecker [2000] 1. Four-limb polydactyly involves both hands and both feet; polydactyly of the hands and feet means that both upper and lower limbs are affected, but not every limb.2. Renal dysplasia is a histologic diagnosis that describes abnormal differentiation of the renal parenchyma.3. Corticomedullary dysplasia is abnormal differentiation of both the cortex and the medulla of the kidney. If focal, renal function may be preserved; if bilateral and extensive, renal failure can result.Other findings associated with MKS. Developmental delay was present in 3/37 survivors (14%) in one study [Slavotinek & Biesecker 2000]. Normal development has also been described at age five years [Gilli et al 1981], six years [Lurie & Wulfsberg 1994], and 14 years [Hamel & ter Haar 1984]. Height ranges from the 25th centile to below the third centile. Fertility has been described; one 16-year-old girl gave birth to a healthy son [Cohen & Javitt 1998]. Three young women required hysterectomy at puberty for complications of endometriosis [Paredes Esteban et al 1996].Findings of unknown significance. Findings that may be either part of the MKS phenotype or coincidental occurrences include cleft palate, high palate, small umbilical herniae, seizures and EEG abnormalities, hearing impairment, albinism, bifid manubrium, supernumerary nipple, single palmar crease [Siala-Giagi et al 1996], sacral dimple, talipes [Siala-Giagi et al 1996], distal tracheo-esophageal fistula, esophageal atresia, and somatic asymmetry.

Genotype-Phenotype CorrelationsNo genotype-phenotype correlation has been reported for mutations in MKKS and either the MKS or the BBS phenotype [Moore et al 2005].

Differential DiagnosisDisorders in which Hydrometrocolpos (HMC) and Postaxial Polydactyly (PAP) OccurBardet-Biedl syndrome (BBS) (see Allelic Disorders) is characterized by rod-cone dystrophy, early childhood-onset truncal obesity, postaxial polydactyly, mild cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction, which is a major cause of morbidity and mortality. Night blindness is usually evident by age seven to eight years. The diagnosis of rod-cone dystrophy is typically made between the ages of two and nine years [Toma et al 2007]. The mean age of legal blindness is 15.5 years. Eleven genes are known to be associated with BBS: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, MKKS/BBS6, BBS7, TTC8/BBS8, BBS9, BBS10, TRIM32/BBS11, BBS12, MKS1/BBS13, and CEP290/BBS14.Ellis-van Creveld syndrome (EVC) [OMIM 225500]. The cardinal phenotypic features of EVC are chondrodysplasia with acromelic growth retardation, polydactyly, ectodermal dysplasia with dystrophy of the nails, and congenital heart disease, most commonly an atrial septal defect [Ruiz-Perez et al 2000, Al-Khenaizan et al 2001]. Several individuals reported as having MKS based on the findings of HMC and PAP had clinical features consistent with EVC [Arcellana et al 1996, Yapar et al 1996]. The two genes known to be associated with EVC and the allelic disorder Weyers acrodental dysostosis [OMIM 193530] are EVC1 [Ruiz-Perez et al 2000] and EVC2 [Galdzicka et al 2002, Ruiz-Perez et al 2003]; however, further locus heterogeneity is suggested by the lack of linkage to either the EVC loci or the MKKS locus in one individual with an EVC phenotype and HMC [Digilio et al 2004]. Other. A 19-year-old woman with lack of Müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydacytly, and tetralogy of Fallot had normal development, normal weight, and no evidence of retinal dystrophy. No MKKS sequence variants were identified by sequence analysis; thus, it is unknown if the individual has a variant form of MKS or a new syndrome [Slavotinek et al 2004]. Disorders in which PAP OccursMesoaxial polydactyly is less common than postaxial polydactyly in individuals with MKS and is more likely to indicate an underlying genetic syndrome such as MKS, BBS, Ellis-van Creveld syndrome, or Pallister-Hall syndrome.VACTERL association. VACTERL is an acronym for an association of physical findings that comprises vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula, renal abnormalities, and limb anomalies including hexadactyly [OMIM 192350]. Clinical similarity between MKS and VACTERL association has been noted on the basis of tracheal abnormalities in individuals with HMC. Pallister-Hall syndrome (PHS) [OMIM 146510]. Overlap of MKS with PHS has been described [el Hammar et al 1998, McCann et al 2006, Kos et al 2008]. PHS is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed adrenal insufficiency. The diagnosis of PHS is based on clinical findings of hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus and renal abnormalities, and family history. GLI3 is the only gene known to be associated with PHS, and both individuals with HMC and PHS were found to have GLI3 mutations (c.2567C>A [McCann et al 2006] and c.2149C>T, predicting p.Glu717X [Kos et al 2008]). PHS is inherited in an autosomal dominant manner. Disorders in which HMC Occurs HMC occurring as part of BBS has been associated with mutations in several other BBS-related genes besides MKKS (for example, BBS10 and BBS12 [Billingsley et al 2010]). Interstitial deletion of chromosome 8q21.11-q24.13 was reported in three young females with HMC who had multiple exostoses that appeared after age three years and craniofacial features consistent with trichorhinophalangeal syndrome type 2 (Langer-Giedion syndrome) [Fryns 1997]. No other cytogenetic abnormalities have been associated with HMC, although two chromosome abnormalities have been associated with vaginal agenesis:De novo translocation [46,XX, t(8;13)(q22.1;q32.1)] in a female with vaginal agenesis and congenital amastia [Amesse et al 1999] Chromosome 13 variant with double satellite stalks on the short arm 46,XX,13pstk+) in a female with vaginal agenesis, posterior displacement of the urethra, small uterus, absent cervix, and bilateral absence of the radii, but no polydactyly [Behera et al 2005]

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with McKusick-Kaufman Syndrome, the following evaluations are recommended:Pelvic ultrasound examination to detect genitourinary malformations (Table 2) Skeletal radiographs to detect osseous polydactyly and syndactyly ECG, echocardiogram, and a renal imaging study to detect congenital heart defects Renal ultrasound examination and a renal imaging study to detect pelvicalyceal abnormalities, renal hypoplasia, or cystic dysplasia of the kidneys Assessment of height, weight, and head circumference and initiation of a carefully maintained growth chart to document obesity that may indicate Bardet-Biedl syndrome (BBS). Determination of developmental status by standard screening tools to detect developmental delay that may indicate BBS. If delays are identified, a more detailed assessment of developmental and cognitive abilities is indicated. In children with weight greater than the 90th centile and/or short stature and/or developmental delay or intellectual disability, ophthalmologic examination and electroretinogram to evaluate for manifestations of BBS Treatment of ManifestationsPrompt surgical repair of the obstruction causing hydrometrocolpos and drainage of the accumulated fluid can be curative.Standard treatment is indicated for the following:Polydactyly and syndactyly Congenital heart defects Anal anomalies and Hirschsprung disease (surgical treatment) Prevention of Secondary ComplicationsRecurrent urinary tract infections and re-stenosis of the vaginal orifice are the most common complications in individuals with MKS following surgical drainage of the HMC [Slavotinek & Biesecker 2000].Care should be taken with anesthesia in the neonatal period if severe hydrometrocolpos causing diaphragmatic compression is present. Gastric decompression and preoxygenation prior to tracheal intubation were used in the anesthetic management of one neonate with severe hydrometrocolpos compressing the diaphragm [Tekin et al 2003].SurveillanceThe following are appropriate:In individuals with renal abnormalities, monitoring of blood pressure and renal function, although no individual with MKS has developed renal failure to date [Slavotinek & Biesecker 2000] In individuals with interim history of constipation, rectal biopsy to exclude Hirschsprung disease Continuing surveillance for manifestations that would establish the diagnosis of BBS including the following: Serial growth measurements to track height and weight until at least age five years to document obesity that can occur with BBS Developmental assessments until at least age five years to detect developmental disabilities that can occur with BBS Regular ophthalmologic examination and electroretinogram (ERG) (if appropriate) after age five years to evaluate for visual signs and symptoms of retinitis pigmentosa [A Verloes, personal communication] As diabetes mellitus is a rare complication of BBS, measurement of blood glucose as appropriate Investigations for rarer complications of BBS, including hearing assessment, dental assessment, electroencephalogram, and thyroid function tests as appropriate Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. McKusick-Kaufman Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMKKS20p12​.2McKusick-Kaufman/Bardet-Biedl syndromes putative chaperoninRetina International Mutations of the McKusick-Kaufman Gene (MKKS)MKKSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for McKusick-Kaufman Syndrome (View All in OMIM) View in own window 236700MCKUSICK-KAUFMAN SYNDROME; MKKS 604896MKKS GENE; MKKSMolecular Genetic PathogenesisThe molecular basis for the differences in phenotype between MKS and BBS remains undetermined. It was first postulated that the differences between the MKS and BBS phenotypes were the result of quantitative or qualitative differences in the protein encoded by MKKS [Katsanis et al 2001, Slavotinek & Biesecker 2001]. It is interesting that mice with a targeted mutation to remove exon 3, which contains the start codon of murine Mkks [Fath et al 2005], have a phenotype that more closely resembles BBS than MKS: the mice develop obesity with high leptin levels and photoreceptor degeneration and have lower levels of social dominance than heterozygotes and wild-type controls. In addition, the males show an absence of flagella in the seminiferous tubules at all ages [Fath et al 2005]. Recent work has shown that at least some mutations in MKKS result in a protein that is more rapidly degraded by the HSC70 interacting protein (CHIP)-dependent, ubiquitin-proteasome pathway than wildtype protein [Hirayama et al 2008]. Among the MKKS mutations tested, both p.His84Tyr and p.Ala242Ser mutant proteins, as found in MKS, underwent accelerated degradation compared to wildtype proteins, but these mutations did not result in an increase in insolubility. As some MKKS mutations proved capable of increasing both the rate of degradation and insolubility, it is plausible that phenotypic severity could be modulated by mutation severity or that the functional ability of the chaperone-dependent protein degradation system could modify the severity of clinical findings [Hirayama et al 2008].However, it is also remotely plausible that the MKS phenotype could be inherited in an autosomal recessive manner, whereas the BBS phenotype could be inherited in a triallelic manner (i.e., resulting from inheritance of mutations at two separate BBS loci or a modifier locus) with the third mutant allele modifying the phenotype to increase clinical severity [Badano et al 2003]. Triallelic inheritance has been demonstrated in families with the BBS phenotype who have affected individuals with three mutations in two different genes associated with BBS [Badano et al 2003, Li et al 2004]. Individuals from the same family with two mutations in a single gene associated with BBS may be clinically unaffected [Badano et al 2003]. However, this mode of inheritance is relatively uncommon in BBS, and data so far suggest that it is unlikely to be present in all BBS cases.Triallelic inheritance has not been demonstrated for the MKS phenotype. In a study on the original Amish family with MKS, in which three affected children were homozygous for both the p.His84Tyr and p.Ala242Ser mutations (see Table 3), sequencing of BBS1, BBS2, BBS3, BBS4, BBS5, and BBS7 in the parents failed to identify any mutations in the coding sequence or splice sites [Nakane & Biesecker 2005]. Involvement of BBS8 in triallelic inheritance for this family was excluded by genotyping [Nakane & Biesecker 2005]. However, this study could not exclude possible triallelic inheritance resulting from a mutation present in a regulatory region or deep within an intron, a microdeletion of a BBS-related gene not detectable by genotyping, or a mutation in a BBS-related gene that was not sequenced [Nakane & Biesecker 2005].Finally, it is interesting to note that 1/22 female Bbs4 homozygous knockout mice was found to have HMC [Eichers et al 2006], whereas HMC was not observed in the Mkks homozygous knockout mouse [Fath et al 2005].Normal allelic variants. MKKS has six exons. The start codon of the gene is in exon 3. Two alternatively spliced 5' exons (exon 1A and exon 1B) are not translated [Stone et al 2000]. Pathologic allelic variants. Mutations have been identified in all of the coding exons of the gene. No known mutation 'hot spot' exists. A high frequency of 'isolated' sequence alterations have been observed in MKKS [Beales et al 2001, Katsanis et al 2001]. Possible explanations other than the failure of sequencing strategies to detect cryptic mutations include triallelic inheritance or autosomal recessive inheritance with a modifying locus [Katsanis et al 2001]. Click here for more detailed information on mutations in MKKS (pdf).Table 3. Selected MKKS Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.250C>Tp.His84Tyr NM_018848​.2
NP_061336​.1c.724G>Tp.Ala242SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The protein encoded by MKKS is a 570-amino acid protein that has the greatest similarity to the Group II chaperonins (archebacterial chaperonins and eukaryotic T complex-related proteins [Slavotinek & Biesecker 2001]). Chaperonins are members of the chaperone protein family or heat shock proteins and stabilize nonnative or unfolded proteins during heat shock or cellular stress. Group I chaperonins (e.g., GroEL in E. coli) are composed of seven identical subunits of 57 kd arranged in two rings stacked back to back. Each subunit has an apical domain, an intermediate domain, and an equatorial domain. The apical domain has hydrophobic residues that bind to nonnative substrate. After binding of the unfolded protein, a co-chaperonin or capping molecule (GroES), and ATP, the chaperonin complex can undergo a conformational change that allows the nonnative protein to be folded in a protected cellular environment [Shtilerman et al 1999]. Note: Two other BBS-associated genes, BBS10 and BBS12, also encode a protein related to the group II chaperonins [Stoetzel et al 2006, Stoetzel et al 2007].Abnormal gene product. The Amish mutation p.His84Tyr was first predicted to affect ATP hydrolysis in the equatorial domain of the protein encoded by MKKS, and thus to disrupt protein function. Both mutations have now been shown to result in protein instability and more rapid protein degradation, as described in Molecular Genetic Pathogenesis [Hirayama et al 2008].