title: Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome).
abstract: Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.
authors.affiliation: Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.forename: Derek
authors.initials: D
authors.lastname: Lim
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Tee
authors.forename: Fatimah
authors.initials: F
authors.lastname: Rahman
authors.forename: John R W
authors.initials: JR
authors.lastname: Yates
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D005091:Exons; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D018392:Genomic Imprinting; D006720:Homozygote; D006801:Humans; D009035:Mothers
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C495732:NLRP2 protein, human