MKKS – Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive ciliopathy characterized by retinal dystrophy, postaxial polydactyly, obesity, hypogonadism and cognitive impairment. MKKS encodes a chaperonin-like protein (BBS6) required for BBSome assembly and ciliary function. Allelic to McKusick-Kaufman syndrome, MKKS mutations underlie a subset of BBS cases, expanding its phenotypic spectrum.

Initial genetic evidence emerged from four unrelated BBS probands harboring biallelic MKKS variants, including the missense c.155G>A (p.Gly52Asp) and nonsense c.792T>A (p.Tyr264Ter) alleles (PMID:10973238). Segregation analysis confirmed trans inheritance in one sib-pair, with all affected individuals homozygous or compound heterozygous for pathogenic MKKS alleles.

The variant spectrum spans missense, nonsense and frameshift mutations, with recurrent private alleles affecting conserved domains. Representative variants include c.155G>A (p.Gly52Asp), c.792T>A (p.Tyr264Ter), c.1316del (p.Thr439IlefsTer7) and c.281del (p.Phe94fs) ([PMID:10973238]).

MKKS-related BBS follows an autosomal recessive inheritance pattern, with segregation documented in consanguineous and non-consanguineous families. One additional affected sibling was reported among progeny of heterozygous parents, supporting full penetrance of biallelic loss-of-function variants.

Functional assays demonstrate that disease-causing MKKS mutants mislocalize from the centrosome and undergo CHIP-mediated ubiquitination and proteasomal degradation, consistent with a loss-of-function mechanism (PMID:18094050). Nuclear-cytoplasmic transport defects mediated by MKKS variants further implicate chromatin remodeling pathways in disease pathogenesis (PMID:28753627).

In summary, robust genetic and experimental data establish MKKS as a bona fide BBS gene under a loss-of-function mechanism. Molecular testing of MKKS informs diagnostic decision-making, carrier screening and genetic counseling in families affected by BBS.

Key Take-home: MKKS sequencing yields a definitive diagnosis in ~10% of BBS cases, enabling tailored management and informing emerging cilia-directed therapies.

References

• Nature Genetics • 2000 • Mutations in MKKS cause Bardet-Biedl syndrome PMID:10973238
• 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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