Germline variants in <i>UHRF1</i> are associated with multilocus imprinting disturbance in humans and mice

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 <i>UHRF1</i>, a gene previously implicated in the maintenance of DNA methylation. To investigate whether the <i>UHRF1</i> c. 2001G>C, p.(Lys667Asn) missense substitution predisposes to abnormal establishment/maintenance of genomic imprinting patterns, a genetically engineered mouse model with a <i>Uhrf1</i> 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 <i>UHRF1</i> variants in affected individuals resulting in an autosomal recessively inherited cause of MLID in humans and expand the range of epigenetic disorders associated with <i>UHRF1.</i>

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Journal
Proceedings of the National Academy of Sciences
Published
2025-08-18
DOI
https://doi.org/10.1073/pnas.2505884122
Citations
1
Primary Topic
Genetic Syndromes and Imprinting
Type
article
Field-Weighted Citation Impact
1.82

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article

Germline variants in UHRF1 are associated with multilocus imprinting disturbance in humans and mice

Fay Rodger, Benoît Lan-Leung, Leonardo Bottolo, Miguel Constância et al.
1 citations
Proceedings of the National Academy of Sciences
Genetic Syndromes and Imprinting
1.82
article

Germline variants in UHRF1 are associated with multilocus imprinting disturbance in humans and mice

Fay Rodger, Benoît Lan-Leung, Leonardo Bottolo, Miguel Constância, Ilona Zvetkova, Jose‐Ezequiel Martín, France Docquier, Mahmoud Y. Issa, Bryndís Yngvadóttir, Ana Luisa Toribio, Wolfgang Fischle, Eguzkine Ochoa, Eamonn R. Maher, Graeme M. Clark, Nozomi Takahashi, Anne C. Ferguson‐Smith, Sunwoo Lee, Emma Hobson, Dounia Foster-Hall
article en
1 citations

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 <i>UHRF1</i>, a gene previously implicated in the maintenance of DNA methylation. To investigate whether the <i>UHRF1</i> c. 2001G>C, p.(Lys667Asn) missense substitution predisposes to abnormal establishment/maintenance of genomic imprinting patterns, a genetically engineered mouse model with a <i>Uhrf1</i> 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 <i>UHRF1</i> variants in affected individuals resulting in an autosomal recessively inherited cause of MLID in humans and expand the range of epigenetic disorders associated with <i>UHRF1.</i>

Proceedings of the National Academy of SciencesVol. 122(34)
Turing Institute (GB), Aston University (GB), Stratasys (Israel) (IL), University of Cambridge (GB), Chapel Allerton Hospital (GB), National Institute for Health and Care Research (GB), Aston Medical (France) (FR), Wellcome/MRC Institute of Metabolic Science (GB), The Alan Turing Institute (GB), MRC Biostatistics Unit (GB), NIHR Cambridge Biomedical Research Centre (GB), King Abdullah University of Science and Technology (SA), Medical Research Council (GB)
National Institute for Health and Care Research, European Commission, Rosetrees Trust, King Abdullah University of Science and Technology, Medical Research Council, Engineering and Physical Sciences Research Council, NIHR Cambridge Biomedical Research Centre
Openalex Percentile: Top 13%
Genetic Syndromes and Imprinting
1.82
DOIOpen Access PDFOpenAlex
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