Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved]
Background: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a key negative regulator of cell growth encoded by a paternally imprinted/maternally expressed gene in humans. Loss-of-function variants in CDKN1C are associated with an overgrowth condition (Beckwith-Wiedemann Syndrome) whereas “gain-of-f...
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| Format: | Article |
| Language: | English |
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F1000 Research Ltd
2019-01-01
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| Series: | F1000Research |
| Online Access: | https://f1000research.com/articles/8-90/v1 |
| _version_ | 1818296223188123648 |
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| author | Jenifer P. Suntharalingham Miho Ishida Federica Buonocore Ignacio del Valle Nita Solanky Charalambos Demetriou Lesley Regan Gudrun E. Moore John C. Achermann |
| author_facet | Jenifer P. Suntharalingham Miho Ishida Federica Buonocore Ignacio del Valle Nita Solanky Charalambos Demetriou Lesley Regan Gudrun E. Moore John C. Achermann |
| author_sort | Jenifer P. Suntharalingham |
| collection | DOAJ |
| description | Background: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a key negative regulator of cell growth encoded by a paternally imprinted/maternally expressed gene in humans. Loss-of-function variants in CDKN1C are associated with an overgrowth condition (Beckwith-Wiedemann Syndrome) whereas “gain-of-function” variants in CDKN1C that increase protein stability cause growth restriction as part of IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia and Genital anomalies). As two families have been reported with CDKN1C mutations who have fetal growth restriction (FGR)/Silver-Russell syndrome (SRS) without adrenal insufficiency, we investigated whether pathogenic variants in CDKN1C could be associated with isolated growth restriction or recurrent loss of pregnancy. Methods: Analysis of published literature was undertaken to review the localisation of variants in CDKN1C associated with IMAGe syndrome or fetal growth restriction. CDKN1C expression in different tissues was analysed in available RNA-Seq data (Human Protein Atlas). Targeted sequencing was used to investigate the critical region of CDKN1C for potential pathogenic variants in SRS (n=58), FGR (n=26), DNA from spontaneous loss of pregnancy (n= 21) and women with recurrent miscarriages (n=71) (total n=176). Results: All published single nucleotide variants associated with IMAGe syndrome are located in a highly-conserved “hot-spot” within the PCNA-binding domain of CDKN1C between codons 272-279. Variants associated with familial growth restriction but normal adrenal function currently affect codons 279 and 281. CDKN1C is highly expressed in the placenta compared to adult tissues, which may contribute to the FGR phenotype and supports a role in pregnancy maintenance. In the patient cohorts studied no pathogenic variants were identified in the PCNA-binding domain of CDKN1C. Conclusion: CDKN1C is a key negative regulator of growth. Variants in a very localised “hot-spot” cause growth restriction, with or without adrenal insufficiency. However, pathogenic variants in this region are not a common cause of isolated fetal growth restriction phenotypes or loss-of-pregnancy/recurrent miscarriages. |
| first_indexed | 2024-12-13T04:00:07Z |
| format | Article |
| id | doaj.art-743bdf2ea6ee423d8db9bf96dd9fd3e8 |
| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-12-13T04:00:07Z |
| publishDate | 2019-01-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-743bdf2ea6ee423d8db9bf96dd9fd3e82022-12-22T00:00:30ZengF1000 Research LtdF1000Research2046-14022019-01-01810.12688/f1000research.15016.116349Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved]Jenifer P. Suntharalingham0Miho Ishida1Federica Buonocore2Ignacio del Valle3Nita Solanky4Charalambos Demetriou5Lesley Regan6Gudrun E. Moore7John C. Achermann8Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKObstetrics and Gynaecology Department, St Mary's Hospital, Imperial College London, London, W2 1NY, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UKBackground: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a key negative regulator of cell growth encoded by a paternally imprinted/maternally expressed gene in humans. Loss-of-function variants in CDKN1C are associated with an overgrowth condition (Beckwith-Wiedemann Syndrome) whereas “gain-of-function” variants in CDKN1C that increase protein stability cause growth restriction as part of IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia and Genital anomalies). As two families have been reported with CDKN1C mutations who have fetal growth restriction (FGR)/Silver-Russell syndrome (SRS) without adrenal insufficiency, we investigated whether pathogenic variants in CDKN1C could be associated with isolated growth restriction or recurrent loss of pregnancy. Methods: Analysis of published literature was undertaken to review the localisation of variants in CDKN1C associated with IMAGe syndrome or fetal growth restriction. CDKN1C expression in different tissues was analysed in available RNA-Seq data (Human Protein Atlas). Targeted sequencing was used to investigate the critical region of CDKN1C for potential pathogenic variants in SRS (n=58), FGR (n=26), DNA from spontaneous loss of pregnancy (n= 21) and women with recurrent miscarriages (n=71) (total n=176). Results: All published single nucleotide variants associated with IMAGe syndrome are located in a highly-conserved “hot-spot” within the PCNA-binding domain of CDKN1C between codons 272-279. Variants associated with familial growth restriction but normal adrenal function currently affect codons 279 and 281. CDKN1C is highly expressed in the placenta compared to adult tissues, which may contribute to the FGR phenotype and supports a role in pregnancy maintenance. In the patient cohorts studied no pathogenic variants were identified in the PCNA-binding domain of CDKN1C. Conclusion: CDKN1C is a key negative regulator of growth. Variants in a very localised “hot-spot” cause growth restriction, with or without adrenal insufficiency. However, pathogenic variants in this region are not a common cause of isolated fetal growth restriction phenotypes or loss-of-pregnancy/recurrent miscarriages.https://f1000research.com/articles/8-90/v1 |
| spellingShingle | Jenifer P. Suntharalingham Miho Ishida Federica Buonocore Ignacio del Valle Nita Solanky Charalambos Demetriou Lesley Regan Gudrun E. Moore John C. Achermann Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved] F1000Research |
| title | Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved] |
| title_full | Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved] |
| title_fullStr | Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved] |
| title_full_unstemmed | Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved] |
| title_short | Analysis of CDKN1C in fetal growth restriction and pregnancy loss [version 1; peer review: 2 approved] |
| title_sort | analysis of cdkn1c in fetal growth restriction and pregnancy loss version 1 peer review 2 approved |
| url | https://f1000research.com/articles/8-90/v1 |
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