Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

Louise E. Docherty; Faisal I. Rezwan; Rebecca L. Poole; Claire L.S. Turner; Emma Kivuva; Eamonn R. Maher; Sarah F. Smithson; Julian P. Hamilton-Shield; Michal Patalan; Maria Gizewska; Jaroslaw Peregud-Pogorzelski; Jasmin Beygo; Karin Buiting; Bernhard Horsthemke; Lukas Soellner; Matthias Begemann; Thomas Eggermann; Emma Baple; Sahar Mansour; I. Karen Temple; Deborah J.G. MacKay

doi:10.1038/ncomms9086

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

Louise E. Docherty
, Faisal I. Rezwan
, Rebecca L. Poole
, Claire L.S. Turner
, Emma Kivuva
, Eamonn R. Maher
, Sarah F. Smithson
, Julian P. Hamilton-Shield
, Michal Patalan
, Maria Gizewska
, Jaroslaw Peregud-Pogorzelski
, Jasmin Beygo
, Karin Buiting
, Bernhard Horsthemke
, Lukas Soellner
, Matthias Begemann
, Thomas Eggermann
, Emma Baple
, Sahar Mansour
, I. Karen Temple

Deborah J.G. MacKay^*

^*Corresponding author for this work

Aston Medical School

Research output: Contribution to journal › Article › peer-review

151 Citations (SciVal)

Abstract

Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

Original language	English
Article number	8086
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9086
Publication status	Published - 1 Sept 2015

Funding

L.E.D. and F.I.R. were supported by the Medical Research Council (MR/J000329/1). J.B., K.B., B.H., L.S. M.B. and T.E. were supported by Bundesministerium für Bildung und Forschung (grant number 01GM1513A and 01GM1513C) and C.T. was supported by an Ipsen Fellowship Grant. The cohort ‘Imprinting Disorders-Finding out Why’ was accrued through the support of the Newlife Foundation for Disabled Children and through support from the Wessex NIHR clinical research network and NIHR Wellcome Southampton clinical research facility. Funding for DNA collection and methylation analysis of normal control samples was provided in part by the National Institutes of Health R01 AI091905-01, R01 AI061471 and R01 HL082925. ERM thanks Action Medical Research for support. L.E.D., F.I.R., M.P., J.B., K.B., L.S., M.B., E.R.M., M.G., B.H., T.E., I.K.T. and D.J.G.M. are members of the COST consortium for Imprinting disorders BM1208 (http://www.imprinting-disorders.eu). J.;B., K.B. and B.H. thank Ludger Klein-Hitpa≈ for supervising exome-sequencing experiments, Christopher Schröder for maintenance of the exome data analysis pipeline and Melanie Heitmann for expert technical assistance. Ethics. All patients were consented into the research study ‘Imprinting disorders— finding out why’ (IDFOW: Southampton and South West Hampshire Research Ethics approval 07/H0502/85) through the UK Comprehensive Local Research network (www.southampton.ac.uk/geneticimprinting/informationpatients/imprin-tingfindingoutwhy.page, accessed on September 2013), with the exception of the patient in family 4 and patients 17–23 who were consented into the research study ‘Disorders caused by imprinting defects’ funded by the Bundesministerium für Bildung und Forschung (BMBF grant 01GM1513), and approved by the Ethical committee of the University Hospital Aachen, Germany.

Funders	Funder number
Aachen University Hospital
University of Southampton Faculty of Medicine, School of Clinical and Experimental Sciences, Southampton SO17 1BJ, UK; NIHR Applied Research Collaboration Wessex, University of Southampton, Southampton SO17 1BJ, UK; Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
National Institutes of Health
National Heart, Lung, and Blood Institute	R01HL082925
National Institute of Allergy and Infectious Diseases (NIAID)	R01AI091905, R01AI061471
Newlife the Charity for Disabled Children
Medical Research Council	MR/J000329/1
Bundesministerium für Bildung und Forschung	01GM1513, 01GM1513A, 01GM1513C

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Docherty, L. E., Rezwan, F. I., Poole, R. L., Turner, C. L. S., Kivuva, E., Maher, E. R., Smithson, S. F., Hamilton-Shield, J. P., Patalan, M., Gizewska, M., Peregud-Pogorzelski, J., Beygo, J., Buiting, K., Horsthemke, B., Soellner, L., Begemann, M., Eggermann, T., Baple, E., Mansour, S., ... MacKay, D. J. G. (2015). Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nature Communications, 6, Article 8086. https://doi.org/10.1038/ncomms9086

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title = "Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans",

abstract = "Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.",

author = "Docherty, \{Louise E.\} and Rezwan, \{Faisal I.\} and Poole, \{Rebecca L.\} and Turner, \{Claire L.S.\} and Emma Kivuva and Maher, \{Eamonn R.\} and Smithson, \{Sarah F.\} and Hamilton-Shield, \{Julian P.\} and Michal Patalan and Maria Gizewska and Jaroslaw Peregud-Pogorzelski and Jasmin Beygo and Karin Buiting and Bernhard Horsthemke and Lukas Soellner and Matthias Begemann and Thomas Eggermann and Emma Baple and Sahar Mansour and Temple, \{I. Karen\} and MacKay, \{Deborah J.G.\}",

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doi = "10.1038/ncomms9086",

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Docherty, LE, Rezwan, FI, Poole, RL, Turner, CLS, Kivuva, E, Maher, ER, Smithson, SF, Hamilton-Shield, JP, Patalan, M, Gizewska, M, Peregud-Pogorzelski, J, Beygo, J, Buiting, K, Horsthemke, B, Soellner, L, Begemann, M, Eggermann, T, Baple, E, Mansour, S, Temple, IK & MacKay, DJG 2015, 'Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans', Nature Communications, vol. 6, 8086. https://doi.org/10.1038/ncomms9086

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T1 - Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

AU - Docherty, Louise E.

AU - Rezwan, Faisal I.

AU - Poole, Rebecca L.

AU - Turner, Claire L.S.

AU - Kivuva, Emma

AU - Maher, Eamonn R.

AU - Smithson, Sarah F.

AU - Hamilton-Shield, Julian P.

AU - Patalan, Michal

AU - Gizewska, Maria

AU - Peregud-Pogorzelski, Jaroslaw

AU - Beygo, Jasmin

AU - Buiting, Karin

AU - Horsthemke, Bernhard

AU - Soellner, Lukas

AU - Begemann, Matthias

AU - Eggermann, Thomas

AU - Baple, Emma

AU - Mansour, Sahar

AU - Temple, I. Karen

AU - MacKay, Deborah J.G.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

AB - Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

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AN - SCOPUS:84940706336

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8086

ER -

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

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