T. Ohta, K. Buiting, H. Kokkonen, S. McCandless, S. Heeger, H

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Molecular Mechanism of Angelman Syndrome in Two Large Families Involves an Imprinting Mutation T. Ohta, K. Buiting, H. Kokkonen, S. McCandless, S. Heeger, H. Leisti, D.J. Driscoll, S.B. Cassidy, B. Horsthemke, R.D. Nicholls The American Journal of Human Genetics Volume 64, Issue 2, Pages 385-396 (February 1999) DOI: 10.1086/302232 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of the two AS families. a, AS-O family. b, AS-F family. The chromosome 15q11-q13 haplotype data for the AS-O family is from Wagstaff et al. (1993), and the haplotype on which the IC mutation arose in each family is boxed. The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical photographs of AS patients. a, b, Maternal half-sisters. c, Cousin with AS, in the AS-O family. d, e, Affected sibs in the AS-F family at 6 and 4 years of age. The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 DNA methylation at SNRPN identifies an imprinting mutation in each AS family. In a, the affected AS-O half-sisters IV-7 (lane 1) and IV-5 (lane 2) have only the unmethylated band after XbaI/NotI digestion of DNA, whereas the mother (III-5) has biparental DNA methylation. In b, the AS-F family DNA is digested with BglII/HpaII (upper panel) or BglII/MspI (lower panel). HpaII/MspI are isochizomers that detect a polymorphic site in SNRPN intron 1 (Saitoh et al. 1997), and comparison of the band patterns allows inference of the parental origin of each band (m or p). See text for further details. mat (m) = maternal; pat (p) = paternal; del = deletion; and N = normal. The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 A 5.5-kb microdeletion of the IC in the AS-O family. a, Molecular map of the AS IC region and extent of the microdeletion (black bar) in the AS-O family. Open boxes indicate probes and a variable number of tandem repeats (VNTR) sequence (Saitoh et al. 1996); arrows indicate PCR primers; E = EcoRI; H = HindIII; B = BamHI; and X = XbaI. b, The use of a BstNI restriction fragment length polymorphism (RFLP) in the IC identifies a deletion in IV-7 and IV-5, since these two half-sisters do not share a visible maternal allele. A = undigested allele, and B = BstNI-digested allele. c, The L48.3I probe detects the distal breakpoint in BamHI-digested DNA. d, The kb25XE probe detects the proximal breakpoint in BamHI-digested DNA. The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 PCR breakpoint analysis of an IC microdeletion in the AS-O family. PCR with primers RN719 and RN720 (upper panel) identifies a breakpoint-specific fragment only in II-1, III-2, IV-1, III-4, IV-3, III-5, IV-5, IV-7, and III-9 in the AS-O family. The use of control primers (PWS-SRO) for PCR shows amplification in all DNA samples (lower panel). The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 6 Summary map of AS microdeletions in the IC and minimal definition of the AS-SRO. The extent of deletions in the new AS families AS-O and AS-F are compared to six previously published deletions (Buiting et al. 1995; Saitoh et al. 1996). The vertical arrow identifies a point mutation in the splice donor site of the IC transcript exon 2, in family AS-C2 (Dittrich et al. 1996). The location of the PWS-SRO is also shown (Buiting et al. 1995; Ohta et al. 1999 [in this issue]). Microdeletions in AS families affect the paternal-to-maternal (pat→mat) switch in the female germline and microdeletions in PWS families affect the maternal-to-paternal (mat→pat) switch in the male germline. Upper blackened boxes indicate exons, and lower blackened boxes and thin horizontal lines indicate DNA probes. The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 7 A 19-kb microdeletion of the IC in the AS-F family. The kb25XE probe detects the proximal breakpoint in KpnI-digested DNA (upper panel), whereas the L48.33II probe detects the distal breakpoint in KpnI-digested DNA (lower panel). The American Journal of Human Genetics 1999 64, 385-396DOI: (10.1086/302232) Copyright © 1999 The American Society of Human Genetics Terms and Conditions