Abstract
BackgroundThe 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.MethodsWe 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.ResultsGlycome 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.ConclusionsThe rescue of ciliogenesis and glycosylation upon reintroduction of WT OFD1 suggests that both contribute to the pathogenesis of JBTS10.
Highlights
The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated
Joubert syndrome (JBTS) is a rare genetic condition characterized by hypotonia, developmental delay, cerebellar dysfunction, a neuroradiologic “molar tooth sign” (MTS), and variable involvement of other systems [1, 2]
The DNA of all family members was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES) as described previously [14,15,16,17]
Summary
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-yearold 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. Loss of OFD1 in animals causes defects in left/right axis development, ciliogenesis, and neurological development [8,9,10]. Based upon its nuclear localization, there is a hypothesis that OFD1 plays a role in chromatin remodeling [13]
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