Germline variants in <i>UHRF1</i> are associated with multilocus imprinting disturbance in humans and mice
Abstract
The investigation of congenital imprinting disorders (CIDs) provides opportunities to elucidate the molecular mechanisms and role of genomic imprinting in development and human disease. Beckwith–Wiedemann spectrum (BWSp) is a prototypic CID resulting from genetic and epigenetic alterations of imprinted genes at chromosome 11p15.5. In up to a quarter of individuals with BWSp, the epigenetic alterations are not confined to 11p15.5 imprinting control regions but also involve other imprinted gene clusters (multilocus imprinting disturbance; MLID). In a consanguineous family with two children diagnosed with BWSp and MLID, the affected individuals were homozygous for a missense variant in UHRF1 , a gene previously implicated in the maintenance of DNA methylation. To investigate whether the UHRF1 c. 2001G>C, p.(Lys667Asn) missense substitution predisposes to abnormal establishment/maintenance of genomic imprinting patterns, a genetically engineered mouse model with a Uhrf1 p.(Lys661Asn) variant was developed. Mice homozygous for the variant born to heterozygous mothers did not display an abnormal phenotype, but homozygotes born to healthy homozygous mothers displayed a range of phenotypes including prenatal lethality. Also, MLID was observed in affected mouse embryos. These findings are consistent with biallelic UHRF1 variants in affected individuals resulting in an autosomal recessively inherited cause of MLID in humans and expand the range of epigenetic disorders associated with UHRF1.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Eguzkine Ochoa
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Ilona Zvetkova
Wellcome-Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge
Sunwoo Liv Lee
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Nozomi Takahashi
Department of Genetics, University of Cambridge
Benoit Lan-Leung
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Emma Hobson
Leeds Clinical Genomics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals National Health Service Trust
Mahmoud Issa
Leeds Clinical Genomics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals National Health Service Trust
Bryndis Yngvadottir
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
France Docquier
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Fay Rodger
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Dounia Foster-Hall
Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre
Graeme Clark
Ana Toribio
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Ezequiel Martin
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Leonardo Bottolo
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Anne C. Ferguson-Smith
Department of Genetics, University of Cambridge
Wolfgang Fischle
Bioscience Program, Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology
Miguel Constancia
Wellcome-Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge
Eamonn R. Maher
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre