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- Abnormal glycosylation in Joubert syndrome type 10
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Abnormal glycosylation in Joubert syndrome type 10 Kane, Megan S; Davids, Mariska; Bond, Michelle R; Adams, Christopher J; Grout, Megan E; Phelps, Ian G; O’Day, Diana R; Dempsey, Jennifer C; Li, Xeuli; Golas, Gretchen; et al.
Abstract
Abstract Background The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and manifested features of Joubert syndrome. Methods We integrated exome sequencing, MALDI-TOF mass spectrometry analyses of plasma and cultured dermal fibroblasts glycomes, and full clinical evaluation of the proband. Analyses of cilia formation and lectin staining were performed by immunofluorescence. Measurement of cellular nucleotide sugar levels was performed with high-performance anion-exchange chromatography with pulsed amperometric detection. Statistical analyses utilized the Student’s and Fisher’s exact t tests. Results Glycome analyses of plasma and cultured dermal fibroblasts identified abnormal N- and O-linked glycosylation profiles. These findings replicated in two unrelated males with OFD1 mutations. Cultured fibroblasts from affected individuals had a defect in ciliogenesis. The proband’s fibroblasts also had an abnormally elevated nuclear sialylation signature and increased total cellular levels of CMP-sialic acid. Ciliogenesis and each glycosylation anomaly were rescued by expression of wild-type OFD1. Conclusions The rescue of ciliogenesis and glycosylation upon reintroduction of WT OFD1 suggests that both contribute to the pathogenesis of JBTS10.
Item Metadata
| Title |
Abnormal glycosylation in Joubert syndrome type 10
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| Creator |
Kane, Megan S; Davids, Mariska; Bond, Michelle R; Adams, Christopher J; Grout, Megan E; Phelps, Ian G; O’Day, Diana R; Dempsey, Jennifer C; Li, Xeuli; Golas, Gretchen; Vezina, Gilbert; Gunay-Aygun, Meral; Hanover, John A; Doherty, Dan; He, Miao; Malicdan, May C V; Gahl, William A; Boerkoel, Cornelius F
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| Publisher |
BioMed Central
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| Date Issued |
2017-03-23
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| Description |
Abstract
Background
The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and manifested features of Joubert syndrome.
Methods
We integrated exome sequencing, MALDI-TOF mass spectrometry analyses of plasma and cultured dermal fibroblasts glycomes, and full clinical evaluation of the proband. Analyses of cilia formation and lectin staining were performed by immunofluorescence. Measurement of cellular nucleotide sugar levels was performed with high-performance anion-exchange chromatography with pulsed amperometric detection. Statistical analyses utilized the Student’s and Fisher’s exact t tests.
Results
Glycome analyses of plasma and cultured dermal fibroblasts identified abnormal N- and O-linked glycosylation profiles. These findings replicated in two unrelated males with OFD1 mutations. Cultured fibroblasts from affected individuals had a defect in ciliogenesis. The proband’s fibroblasts also had an abnormally elevated nuclear sialylation signature and increased total cellular levels of CMP-sialic acid. Ciliogenesis and each glycosylation anomaly were rescued by expression of wild-type OFD1.
Conclusions
The rescue of ciliogenesis and glycosylation upon reintroduction of WT OFD1 suggests that both contribute to the pathogenesis of JBTS10.
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| Subject | |
| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2018-05-29
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution 4.0 International (CC BY 4.0)
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| DOI |
10.14288/1.0367875
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| URI | |
| Affiliation | |
| Citation |
Cilia. 2017 Mar 23;6(1):2
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| Publisher DOI |
10.1186/s13630-017-0048-6
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| Peer Review Status |
Reviewed
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| Scholarly Level |
Faculty
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| Copyright Holder |
The Author(s)
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Rights
Attribution 4.0 International (CC BY 4.0)