MKS1 – Joubert Syndrome

MKS1 encodes a B9 domain–containing protein localized to the ciliary transition zone and basal body, essential for primary cilium formation and epithelial morphogenesis. Pathogenic variants in MKS1 cause Meckel-Gruber syndrome and have been implicated in Joubert syndrome (MONDO:0018772) with autosomal recessive inheritance. Clinical presentation of MKS1-related Joubert syndrome (JS) includes the characteristic molar tooth sign, hypotonia, ataxia, and variable organ involvement, reflecting a spectrum from lethal embryonic defects to mild neurodevelopmental ciliopathies.

Biallelic MKS1 variants have been identified in 16 probands across at least ten unrelated families with JS ([PMID:27570071]; [PMID:27377014]; [PMID:33193692]; [PMID:24886560]; [PMID:26490104]). Segregation of homozygous and compound heterozygous alleles in consanguineous pedigrees confirms autosomal recessive transmission with 4 affected relatives observed in one family ([PMID:27570071]).

The variant spectrum includes non-truncating alleles (in-frame deletions such as c.1115_1117del (p.Ser372del)), missense changes (e.g., c.240G>T (p.Trp80Cys)), splice–site and loss-of-function mutations (frameshifts and nonsense). Both hypomorphic and null alleles contribute to phenotypic heterogeneity, and founder deletions (e.g., intronic c.1408-35_1408-7del29) have been reported in specific populations ([PMID:27377014]).

Cellular assays demonstrate that JS-associated MKS1 mutations impair ciliary localization of ARL13B and INPP5E, reduce cilium number and alter ciliary length in patient fibroblasts, and fail to rescue spheroid morphogenesis in three-dimensional culture ([PMID:26490104]). In vitro siRNA knockdown of MKS1 disrupts centriole migration and ciliogenesis in epithelial cell lines, and coimmunoprecipitation confirms interaction with meckelin, implicating a loss-of-function mechanism ([PMID:17185389]).

Animal models further support pathogenicity: Mks1 knockout mice exhibit preaxial polydactyly, brain malformations and renal cystic dysplasia, accompanied by deregulated Wnt/β-catenin and Hh signaling ([PMID:23454480]). Zebrafish mks1 mutants display variable ciliary phenotypes consistent with JS and related syndromes, underscoring tissue-specific functions of MKS1 in vertebrate development ([PMID:36533556]).

Together, genetic and experimental data strongly support MKS1 as a recessive JS gene. While the full allelic series and phenotype modifiers continue to emerge, current evidence meets ClinGen criteria for a Strong gene-disease association. Key Take-home: MKS1 mutation analysis should be included in diagnostic panels for Joubert syndrome to inform genetic counseling and management.

References

• American journal of medical genetics. Part A • 2016 • Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies PMID:27570071
• European journal of medical genetics • 2016 • MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum PMID:27377014
• Frontiers in genetics • 2020 • Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome PMID:33193692
• Orphanet journal of rare diseases • 2014 • Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome PMID:24886560
• Journal of medical genetics • 2016 • MKS1 regulates ciliary INPP5E levels in Joubert syndrome PMID:26490104
• Developmental biology • 2013 • Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome PMID:23454480
• Disease models & mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants PMID:36533556

Evidence Based Scoring (AI generated)