TY - JOUR
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, E.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, M.
AU - Eggermann, T.
AU - Baple, Emma
AU - Mansour, S.
AU - Temple, I. Kare
AU - MacKay, Deborah J. G.
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
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.
KW - Abortion, Spontaneous/genetics
KW - Adolescent
KW - Adult
KW - Autistic Disorder/genetics
KW - Autoantigens/genetics
KW - Beckwith-Wiedemann Syndrome/genetics
KW - Computer Simulation
KW - DNA Copy Number Variations
KW - DNA Methylation
KW - Diabetes Mellitus/genetics
KW - Epigenesis, Genetic
KW - Female
KW - Genomic Imprinting/genetics
KW - Humans
KW - Hydatidiform Mole/genetics
KW - Infant, Newborn, Diseases/genetics
KW - Infertility, Female/genetics
KW - Male
KW - Mitochondrial Proteins
KW - Mothers
KW - Mutation
KW - Nuclear Proteins
KW - Obesity/genetics
KW - Polymerase Chain Reaction
KW - Pregnancy
KW - Sequence Analysis, DNA
KW - Silver-Russell Syndrome/genetics
KW - Twins, Monozygotic
KW - Uterine Neoplasms/genetics
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=84940706336&partnerID=8YFLogxK
U2 - 10.1038/ncomms9086
DO - 10.1038/ncomms9086
M3 - Article
C2 - 26323243
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 8086
ER -
