Mouse imprinting defect mutations that model Angelman syndrome.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders resulting from deficiency of imprinted gene expression from paternal or maternal chromosome 15q11-15q13, respectively. In humans, expression of the imprinted genes is under control of a bipartite cis-acting imprinting center (IC). Families with deletions causing PWS imprinting defects localize the PWS-IC to 4.3 kb overlapping with SNRPN exon 1. Families with deletions causing AS imprinting defects localize the AS-IC to 880 bp 35 kb upstream of the PWS-IC. We report two mouse mutations resulting in defects similar to that seen in AS patients with deletion of the AS-IC. An insertion/duplication mutation 13 kb upstream of Snrpn exon 1 resulted in lack of methylation at the maternal Snrpn promoter, activation of maternally repressed genes, and decreased expression of paternally repressed genes. The acquisition of a paternal epigenotype on the maternal chromosome in the mutant mice was demonstrated by the ability to rescue the lethality and growth retardation in a mouse model of a PWS imprinting defect. A second mutation, an 80-kb deletion extending upstream of the first mutation, caused a similar imprinting defect with variable penetrance. These results suggest that there is a mouse functional equivalent to the human AS-IC.
Wu
Mei-Yi
MY
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Chen
Ken-Shiung
KS
Bressler
Jan
J
Hou
Aihua
A
Tsai
Ting-Fen
TF
Beaudet
Arthur L
AL
D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001483:Base Sequence; D015139:Blotting, Southern; D015153:Blotting, Western; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D017931:DNA Primers; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics; D055517:snRNP Core Proteins
D001324:Autoantigens; D017931:DNA Primers; D017411:Ribonucleoproteins, Small Nuclear; C526417:SNRPN protein, human; D055517:snRNP Core Proteins