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Abnormal glycosylation in Joubert syndrome type 10
Megan S Kane1,2, Mariska Davids1, Michelle R Bond3
1NIH Undiagnosed Disease Program, Common Fund, Office of the Director, and National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA.
Cilia
|March 28, 2017
Summary
Joubert syndrome type 10 (JBTS10) pathogenesis involves disrupted ciliogenesis and abnormal glycosylation. Restoring the OFD1 gene corrected these defects, indicating their crucial role in JBTS10 development.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Joubert syndrome type 10 (JBTS10) pathogenesis requires understanding deregulated homeostatic processes.
- A 5-year-old boy with JBTS10, carrying an OFD1 mutation (p.Gln886Lysfs*2), presented with characteristic features.
Purpose of the Study:
- To investigate the molecular mechanisms underlying JBTS10 pathogenesis.
- To evaluate the roles of ciliogenesis and glycosylation in OFD1-related disorders.
Main Methods:
- Integrated exome sequencing, plasma and fibroblast glycome analysis (MALDI-TOF MS).
- Immunofluorescence for cilia formation and lectin staining.
- High-performance anion-exchange chromatography for cellular nucleotide sugar levels.
Main Results:
- Abnormal N- and O-linked glycosylation profiles in plasma and fibroblasts of affected individuals.
- Defective ciliogenesis and elevated nuclear sialylation (CMP-sialic acid) in proband fibroblasts.
- Rescue of both ciliogenesis and glycosylation defects upon expression of wild-type OFD1.
Conclusions:
- Disrupted ciliogenesis and aberrant glycosylation are key contributors to JBTS10 pathogenesis.
- Restoration of OFD1 function rescues both cellular defects, confirming their pathogenic relevance.
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