Analysis of CDKN1C in fetal growth restriction and pregnancy loss
Autor: | John C. Achermann, Ignacio del Valle, Miho Ishida, Jenifer P. Suntharalingham, Lesley Regan, Charalambos Demetriou, Gudrun E. Moore, Nita Solanky, Federica Buonocore |
---|---|
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
placenta Biology recurrent miscarriage General Biochemistry Genetics and Molecular Biology fetal growth restriction 03 medical and health sciences 0302 clinical medicine Placenta Recurrent miscarriage medicine Adrenal insufficiency General Pharmacology Toxicology and Pharmaceutics IMAGe Syndrome 030304 developmental biology Genetics 0303 health sciences Pregnancy General Immunology and Microbiology Silver–Russell syndrome Articles General Medicine medicine.disease Phenotype Hypoplasia IMAGe syndrome CDKN1C 030104 developmental biology medicine.anatomical_structure adrenal 030220 oncology & carcinogenesis Silver-Russell syndrome intra-uterine growth restriction Research Article |
Zdroj: | F1000Research |
ISSN: | 2046-1402 |
Popis: | 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 three 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=66), FGR (n=37), DNA from spontaneous loss of pregnancy (n= 22) and women with recurrent miscarriages (n=78) (total n=203). 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. |
Databáze: | OpenAIRE |
Externí odkaz: |