Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes
Abstract Background Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGD...
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-020-1313-0 |
| _version_ | 1818661754688765952 |
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| author | Leigh C. Carmody Hannah Blau Daniel Danis Xingman A. Zhang Jean-Philippe Gourdine Nicole Vasilevsky Peter Krawitz Miles D. Thompson Peter N. Robinson |
| author_facet | Leigh C. Carmody Hannah Blau Daniel Danis Xingman A. Zhang Jean-Philippe Gourdine Nicole Vasilevsky Peter Krawitz Miles D. Thompson Peter N. Robinson |
| author_sort | Leigh C. Carmody |
| collection | DOAJ |
| description | Abstract Background Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage). Results We addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities. Conclusions IGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs. |
| first_indexed | 2024-12-17T04:50:05Z |
| format | Article |
| id | doaj.art-7fe7d9f45461427abe3ec22868d08bea |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-17T04:50:05Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-7fe7d9f45461427abe3ec22868d08bea2022-12-21T22:02:55ZengBMCOrphanet Journal of Rare Diseases1750-11722020-02-0115111310.1186/s13023-020-1313-0Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genesLeigh C. Carmody0Hannah Blau1Daniel Danis2Xingman A. Zhang3Jean-Philippe Gourdine4Nicole Vasilevsky5Peter Krawitz6Miles D. Thompson7Peter N. Robinson8The Jackson Laboratory for Genomic MedicineThe Jackson Laboratory for Genomic MedicineThe Jackson Laboratory for Genomic MedicineThe Jackson Laboratory for Genomic MedicineOregon Health & Science UniversityOregon Health & Science UniversityInstitute of Genomic Statistics and Bioinformatics, University of BonnDepartment of Pediatrics, UCSD School of MedicineThe Jackson Laboratory for Genomic MedicineAbstract Background Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage). Results We addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities. Conclusions IGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs.https://doi.org/10.1186/s13023-020-1313-0GPI-anchorGlycosylphosphatidylinositolsCongenital disorders of glycosylationHuman phenotype ontology |
| spellingShingle | Leigh C. Carmody Hannah Blau Daniel Danis Xingman A. Zhang Jean-Philippe Gourdine Nicole Vasilevsky Peter Krawitz Miles D. Thompson Peter N. Robinson Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes Orphanet Journal of Rare Diseases GPI-anchor Glycosylphosphatidylinositols Congenital disorders of glycosylation Human phenotype ontology |
| title | Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes |
| title_full | Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes |
| title_fullStr | Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes |
| title_full_unstemmed | Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes |
| title_short | Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes |
| title_sort | significantly different clinical phenotypes associated with mutations in synthesis and transamidase remodeling glycosylphosphatidylinositol gpi anchor biosynthesis genes |
| topic | GPI-anchor Glycosylphosphatidylinositols Congenital disorders of glycosylation Human phenotype ontology |
| url | https://doi.org/10.1186/s13023-020-1313-0 |
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