MKKS – McKusick-Kaufman syndrome

McKusick-Kaufman syndrome is a rare autosomal recessive disorder caused by biallelic mutations in the MKKS gene, presenting with a clinical triad of hydrometrocolpos, postaxial polydactyly, and congenital heart disease. The hallmark phenotypes correspond to HP:0030010, HP:0100259, and HP:0001627.

Initial positional cloning in the Old Order Amish and a sporadic non-Amish case identified homozygous MKKS missense alleles p.His84Tyr and p.Ala242Ser in affected siblings and a compound heterozygous p.Tyr37Cys/p.Gly409fs genotype in another patient, conclusively linking MKKS to McKusick-Kaufman syndrome (PMID:10802661). Subsequent multicenter studies have reported at least 8 unrelated probands with biallelic MKKS variants, and segregation has been demonstrated in two families (PMID:10973238; PMID:12107442).

The variant spectrum includes missense substitutions (n=5) and frameshift/truncating alleles (n=3) across exons 1–9, without evidence for triallelic inheritance. Recurrent alleles such as c.724G>T (p.Ala242Ser) and c.250C>T (p.His84Tyr) account for a significant proportion of cases in founder populations.

Functional assays reveal that MKKS encodes a chaperonin-like protein essential for centrosomal trafficking; disease-causing mutants are aberrantly degraded via CHIP-mediated ubiquitination and fail to localize to the centrosome (PMID:18094050). Furthermore, the MKKS^H84Y;A242S allele selectively impairs nuclear–cytoplasmic transport of SMARCC1 in zebrafish models, elucidating a mechanism for congenital heart defects (PMID:28753627).

Collectively, these data support a loss-of-function mechanism for MKKS in McKusick-Kaufman syndrome characterized by defective protein folding and subcellular trafficking. The consistency of inheritance, variant pathogenicity, and functional concordance over >20 years establishes a Definitive gene–disease relationship.

Key Take-home: Genetic testing of MKKS enables early, accurate diagnosis of McKusick-Kaufman syndrome, guiding perinatal management and genetic counseling.

References

• Nature genetics • 2000 • Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. PMID:10802661
• Nature genetics • 2000 • Mutations in MKKS cause Bardet-Biedl syndrome. PMID:10973238
• Human genetics • 2002 • Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients. PMID:12107442
• Molecular biology of the cell • 2008 • MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination. PMID:18094050
• PLoS genetics • 2017 • Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein. PMID:28753627

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