Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2001 Dec;38(12):834–845. doi: 10.1136/jmg.38.12.834

Distinct phenotypes distinguish the molecular classes of Angelman syndrome

A Lossie 1, M Whitney 1, D Amidon 1, H Dong 1, P Chen 1, D Theriaque 1, A Hutson 1, R Nicholls 1, R Zori 1, C Williams 1, D Driscoll 1
PMCID: PMC1734773  PMID: 11748306

Abstract

BACKGROUND—Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures.
METHODS—We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations.
RESULTS—In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes.
CONCLUSIONS—Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.


Keywords: Angelman syndrome; genotype-phenotype correlations; DNA methylation; 15q11-q13

Full Text

The Full Text of this article is available as a PDF (180.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baumer A., Balmer D., Schinzel A. Screening for UBE3A gene mutations in a group of Angelman syndrome patients selected according to non-stringent clinical criteria. Hum Genet. 1999 Dec;105(6):598–602. doi: 10.1007/s004399900197. [DOI] [PubMed] [Google Scholar]
  2. Beer-Romero P., Glass S., Rolfe M. Antisense targeting of E6AP elevates p53 in HPV-infected cells but not in normal cells. Oncogene. 1997 Feb 6;14(5):595–602. doi: 10.1038/sj.onc.1200872. [DOI] [PubMed] [Google Scholar]
  3. Bird A. P., Wolffe A. P. Methylation-induced repression--belts, braces, and chromatin. Cell. 1999 Nov 24;99(5):451–454. doi: 10.1016/s0092-8674(00)81532-9. [DOI] [PubMed] [Google Scholar]
  4. Bottani A., Robinson W. P., DeLozier-Blanchet C. D., Engel E., Morris M. A., Schmitt B., Thun-Hohenstein L., Schinzel A. Angelman syndrome due to paternal uniparental disomy of chromosome 15: a milder phenotype? Am J Med Genet. 1994 May 15;51(1):35–40. doi: 10.1002/ajmg.1320510109. [DOI] [PubMed] [Google Scholar]
  5. Bürger J., Kunze J., Sperling K., Reis A. Phenotypic differences in Angelman syndrome patients: imprinting mutations show less frequently microcephaly and hypopigmentation than deletions. Am J Med Genet. 1996 Dec 11;66(2):221–226. doi: 10.1002/(SICI)1096-8628(19961211)66:2<221::AID-AJMG19>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
  6. Cattanach B. M., Barr J. A., Beechey C. V., Martin J., Noebels J., Jones J. A candidate model for Angelman syndrome in the mouse. Mamm Genome. 1997 Jul;8(7):472–478. doi: 10.1007/s003359900479. [DOI] [PubMed] [Google Scholar]
  7. Christian S. L., Bhatt N. K., Martin S. A., Sutcliffe J. S., Kubota T., Huang B., Mutirangura A., Chinault A. C., Beaudet A. L., Ledbetter D. H. Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb. Genome Res. 1998 Feb;8(2):146–157. doi: 10.1101/gr.8.2.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clayton-Smith J., Driscoll D. J., Waters M. F., Webb T., Andrews T., Malcolm S., Pembrey M. E., Nicholls R. D. Difference in methylation patterns within the D15S9 region of chromosome 15q11-13 in first cousins with Angelman syndrome and Prader-Willi syndrome. Am J Med Genet. 1993 Oct 1;47(5):683–686. doi: 10.1002/ajmg.1320470519. [DOI] [PubMed] [Google Scholar]
  9. Dan B., Boyd S. G., Christiaens F., Courtens W., Van Maldergem L., Kahn A. Atypical features in Angelman syndrome due to imprinting defect of uniparental disomy of chromosome 15. Neuropediatrics. 2000 Apr;31(2):109–110. doi: 10.1055/s-2000-7485. [DOI] [PubMed] [Google Scholar]
  10. Dhar M., Webb L. S., Smith L., Hauser L., Johnson D., West D. B. A novel ATPase on mouse chromosome 7 is a candidate gene for increased body fat. Physiol Genomics. 2000 Nov 9;4(1):93–100. doi: 10.1152/physiolgenomics.2000.4.1.93. [DOI] [PubMed] [Google Scholar]
  11. Dittrich B., Buiting K., Gross S., Horsthemke B. Characterization of a methylation imprint in the Prader-Willi syndrome chromosome region. Hum Mol Genet. 1993 Dec;2(12):1995–1999. doi: 10.1093/hmg/2.12.1995. [DOI] [PubMed] [Google Scholar]
  12. Driscoll D. J., Waters M. F., Williams C. A., Zori R. T., Glenn C. C., Avidano K. M., Nicholls R. D. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics. 1992 Aug;13(4):917–924. doi: 10.1016/0888-7543(92)90001-9. [DOI] [PubMed] [Google Scholar]
  13. Dupont J. M., Le Tessier D., Rabineau D., Cuisset L., Vasseur C., Jeanpierre M., Delpech M., Pinton F., Ponsot G., Denavit M. F. Unexpected Angelman syndrome molecular defect in a girl displaying clinical features of Prader-Willi syndrome. J Med Genet. 1999 Aug;36(8):652–654. [PMC free article] [PubMed] [Google Scholar]
  14. Fang P., Lev-Lehman E., Tsai T. F., Matsuura T., Benton C. S., Sutcliffe J. S., Christian S. L., Kubota T., Halley D. J., Meijers-Heijboer H. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet. 1999 Jan;8(1):129–135. doi: 10.1093/hmg/8.1.129. [DOI] [PubMed] [Google Scholar]
  15. Freeman S. B., May K. M., Pettay D., Fernhoff P. M., Hassold T. J. Paternal uniparental disomy in a child with a balanced 15;15 translocation and Angelman syndrome. Am J Med Genet. 1993 Mar 1;45(5):625–630. doi: 10.1002/ajmg.1320450522. [DOI] [PubMed] [Google Scholar]
  16. Fridman C., Santos M., Ferrari I., Koiffmann C. P. A further Angelman syndrome patient with UPD15 due to paternal meiosis II nondisjunction. Clin Genet. 2000 Jan;57(1):86–87. doi: 10.1034/j.1399-0004.2000.570114.x. [DOI] [PubMed] [Google Scholar]
  17. Fridman C., Varela M. C., Kok F., Diament A., Koiffmann C. P. Paternal UPD15: further genetic and clinical studies in four Angelman syndrome patients. Am J Med Genet. 2000 Jun 19;92(5):322–327. doi: 10.1002/1096-8628(20000619)92:5<322::aid-ajmg6>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  18. Fridman C., Varela M. C., Nicholls R. D., Koiffmann C. P. Unusual clinical features in an Angelman syndrome patient with uniparental disomy due to a translocation 15q15q. Clin Genet. 1998 Oct;54(4):303–308. doi: 10.1034/j.1399-0004.1998.5440407.x. [DOI] [PubMed] [Google Scholar]
  19. Frischmeyer P. A., Dietz H. C. Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet. 1999;8(10):1893–1900. doi: 10.1093/hmg/8.10.1893. [DOI] [PubMed] [Google Scholar]
  20. Fung D. C., Yu B., Cheong K. F., Smith A., Trent R. J. UBE3A "mutations" in two unrelated and phenotypically different Angelman syndrome patients. Hum Genet. 1998 Apr;102(4):487–492. doi: 10.1007/s004390050727. [DOI] [PubMed] [Google Scholar]
  21. Gabriel J. M., Merchant M., Ohta T., Ji Y., Caldwell R. G., Ramsey M. J., Tucker J. D., Longnecker R., Nicholls R. D. A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9258–9263. doi: 10.1073/pnas.96.16.9258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gillessen-Kaesbach G., Albrecht B., Passarge E., Horsthemke B. Further patient with Angelman syndrome due to paternal disomy of chromosome 15 and a milder phenotype. Am J Med Genet. 1995 Apr 10;56(3):328–329. doi: 10.1002/ajmg.1320560324. [DOI] [PubMed] [Google Scholar]
  23. Gillessen-Kaesbach G., Demuth S., Thiele H., Theile U., Lich C., Horsthemke B. A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect. Eur J Hum Genet. 1999 Sep;7(6):638–644. doi: 10.1038/sj.ejhg.5200362. [DOI] [PubMed] [Google Scholar]
  24. Glenn C. C., Driscoll D. J., Yang T. P., Nicholls R. D. Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes. Mol Hum Reprod. 1997 Apr;3(4):321–332. doi: 10.1093/molehr/3.4.321. [DOI] [PubMed] [Google Scholar]
  25. Glenn C. C., Nicholls R. D., Robinson W. P., Saitoh S., Niikawa N., Schinzel A., Horsthemke B., Driscoll D. J. Modification of 15q11-q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum Mol Genet. 1993 Sep;2(9):1377–1382. doi: 10.1093/hmg/2.9.1377. [DOI] [PubMed] [Google Scholar]
  26. Glenn C. C., Saitoh S., Jong M. T., Filbrandt M. M., Surti U., Driscoll D. J., Nicholls R. D. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet. 1996 Feb;58(2):335–346. [PMC free article] [PubMed] [Google Scholar]
  27. Gray T. A., Saitoh S., Nicholls R. D. An imprinted, mammalian bicistronic transcript encodes two independent proteins. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5616–5621. doi: 10.1073/pnas.96.10.5616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Greger V., Knoll J. H., Wagstaff J., Woolf E., Lieske P., Glatt H., Benn P. A., Rosengren S. S., Lalande M. Angelman syndrome associated with an inversion of chromosome 15q11.2q24.3. Am J Hum Genet. 1997 Mar;60(3):574–580. [PMC free article] [PubMed] [Google Scholar]
  29. Gyftodimou J., Karadima G., Pandelia E., Vassilopoulos D., Petersen M. B. Angelman syndrome with uniparental disomy due to paternal meiosis II nondisjunction. Clin Genet. 1999 Jun;55(6):483–486. doi: 10.1034/j.1399-0004.1999.550615.x. [DOI] [PubMed] [Google Scholar]
  30. Hentze M. W., Kulozik A. E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell. 1999 Feb 5;96(3):307–310. doi: 10.1016/s0092-8674(00)80542-5. [DOI] [PubMed] [Google Scholar]
  31. Herzing L. B., Kim S. J., Cook E. H., Jr, Ledbetter D. H. The human aminophospholipid-transporting ATPase gene ATP10C maps adjacent to UBE3A and exhibits similar imprinted expression. Am J Hum Genet. 2001 May 11;68(6):1501–1505. doi: 10.1086/320616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Huibregtse J. M., Scheffner M., Howley P. M. Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol Cell Biol. 1993 Feb;13(2):775–784. doi: 10.1128/mcb.13.2.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Imessaoudene B., Bonnefont J. P., Royer G., Cormier-Daire V., Lyonnet S., Lyon G., Munnich A., Amiel J. MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. J Med Genet. 2001 Mar;38(3):171–174. doi: 10.1136/jmg.38.3.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Jay P., Rougeulle C., Massacrier A., Moncla A., Mattei M. G., Malzac P., Roëckel N., Taviaux S., Lefranc J. L., Cau P. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet. 1997 Nov;17(3):357–361. doi: 10.1038/ng1197-357. [DOI] [PubMed] [Google Scholar]
  35. Jiang Y. H., Armstrong D., Albrecht U., Atkins C. M., Noebels J. L., Eichele G., Sweatt J. D., Beaudet A. L. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998 Oct;21(4):799–811. doi: 10.1016/s0896-6273(00)80596-6. [DOI] [PubMed] [Google Scholar]
  36. Johnson D. K., Stubbs L. J., Culiat C. T., Montgomery C. S., Russell L. B., Rinchik E. M. Molecular analysis of 36 mutations at the mouse pink-eyed dilution (p) locus. Genetics. 1995 Dec;141(4):1563–1571. doi: 10.1093/genetics/141.4.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Jong M. T., Gray T. A., Ji Y., Glenn C. C., Saitoh S., Driscoll D. J., Nicholls R. D. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum Mol Genet. 1999 May;8(5):783–793. doi: 10.1093/hmg/8.5.783. [DOI] [PubMed] [Google Scholar]
  38. Kao W. H., Beaudenon S. L., Talis A. L., Huibregtse J. M., Howley P. M. Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. J Virol. 2000 Jul;74(14):6408–6417. doi: 10.1128/jvi.74.14.6408-6417.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kishino T., Lalande M., Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997 Jan;15(1):70–73. doi: 10.1038/ng0197-70. [DOI] [PubMed] [Google Scholar]
  40. Kubota T., Aradhya S., Macha M., Smith A. C., Surh L. C., Satish J., Verp M. S., Nee H. L., Johnson A., Christan S. L. Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis. J Med Genet. 1996 Dec;33(12):1011–1014. doi: 10.1136/jmg.33.12.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kubota T., Das S., Christian S. L., Baylin S. B., Herman J. G., Ledbetter D. H. Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997 May;16(1):16–17. doi: 10.1038/ng0597-15. [DOI] [PubMed] [Google Scholar]
  42. Kubota T., Sutcliffe J. S., Aradhya S., Gillessen-Kaesbach G., Christian S. L., Horsthemke B., Beaudet A. L., Ledbetter D. H. Validation studies of SNRPN methylation as a diagnostic test for Prader-Willi syndrome. Am J Med Genet. 1996 Dec 2;66(1):77–80. doi: 10.1002/(SICI)1096-8628(19961202)66:1<77::AID-AJMG18>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  43. Kumar S., Talis A. L., Howley P. M. Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem. 1999 Jun 25;274(26):18785–18792. doi: 10.1074/jbc.274.26.18785. [DOI] [PubMed] [Google Scholar]
  44. Laan L. A., v Haeringen A., Brouwer O. F. Angelman syndrome: a review of clinical and genetic aspects. Clin Neurol Neurosurg. 1999 Sep;101(3):161–170. doi: 10.1016/s0303-8467(99)00030-x. [DOI] [PubMed] [Google Scholar]
  45. Lossie A. C., Driscoll D. J. Transmission of Angelman syndrome by an affected mother. Genet Med. 1999 Sep-Oct;1(6):262–266. doi: 10.1097/00125817-199909000-00004. [DOI] [PubMed] [Google Scholar]
  46. Malcolm S., Clayton-Smith J., Nichols M., Robb S., Webb T., Armour J. A., Jeffreys A. J., Pembrey M. E. Uniparental paternal disomy in Angelman's syndrome. Lancet. 1991 Mar 23;337(8743):694–697. doi: 10.1016/0140-6736(91)90278-w. [DOI] [PubMed] [Google Scholar]
  47. Malzac P., Webber H., Moncla A., Graham J. M., Kukolich M., Williams C., Pagon R. A., Ramsdell L. A., Kishino T., Wagstaff J. Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet. 1998 Jun;62(6):1353–1360. doi: 10.1086/301877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Matsuura T., Sutcliffe J. S., Fang P., Galjaard R. J., Jiang Y. H., Benton C. S., Rommens J. M., Beaudet A. L. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997 Jan;15(1):74–77. doi: 10.1038/ng0197-74. [DOI] [PubMed] [Google Scholar]
  49. Meguro M., Kashiwagi A., Mitsuya K., Nakao M., Kondo I., Saitoh S., Oshimura M. A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome. Nat Genet. 2001 May;28(1):19–20. doi: 10.1038/ng0501-19. [DOI] [PubMed] [Google Scholar]
  50. Meguro M., Mitsuya K., Nomura N., Kohda M., Kashiwagi A., Nishigaki R., Yoshioka H., Nakao M., Oishi M., Oshimura M. Large-scale evaluation of imprinting status in the Prader-Willi syndrome region: an imprinted direct repeat cluster resembling small nucleolar RNA genes. Hum Mol Genet. 2001 Feb 15;10(4):383–394. doi: 10.1093/hmg/10.4.383. [DOI] [PubMed] [Google Scholar]
  51. Minassian B. A., DeLorey T. M., Olsen R. W., Philippart M., Bronstein Y., Zhang Q., Guerrini R., Van Ness P., Livet M. O., Delgado-Escueta A. V. Angelman syndrome: correlations between epilepsy phenotypes and genotypes. Ann Neurol. 1998 Apr;43(4):485–493. doi: 10.1002/ana.410430412. [DOI] [PubMed] [Google Scholar]
  52. Moncla A., Malzac P., Livet M. O., Voelckel M. A., Mancini J., Delaroziere J. C., Philip N., Mattei J. F. Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling. J Med Genet. 1999 Jul;36(7):554–560. [PMC free article] [PubMed] [Google Scholar]
  53. Moncla A., Malzac P., Voelckel M. A., Auquier P., Girardot L., Mattei M. G., Philip N., Mattei J. F., Lalande M., Livet M. O. Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur J Hum Genet. 1999 Feb-Mar;7(2):131–139. doi: 10.1038/sj.ejhg.5200258. [DOI] [PubMed] [Google Scholar]
  54. Moore T., Haig D. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 1991 Feb;7(2):45–49. doi: 10.1016/0168-9525(91)90230-N. [DOI] [PubMed] [Google Scholar]
  55. Mutirangura A., Greenberg F., Butler M. G., Malcolm S., Nicholls R. D., Chakravarti A., Ledbetter D. H. Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy. Hum Mol Genet. 1993 Feb;2(2):143–151. doi: 10.1093/hmg/2.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Nakao M., Sutcliffe J. S., Durtschi B., Mutirangura A., Ledbetter D. H., Beaudet A. L. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum Mol Genet. 1994 Feb;3(2):309–315. doi: 10.1093/hmg/3.2.309. [DOI] [PubMed] [Google Scholar]
  57. Nicholls R. D., Saitoh S., Horsthemke B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 1998 May;14(5):194–200. doi: 10.1016/s0168-9525(98)01432-2. [DOI] [PubMed] [Google Scholar]
  58. Oda H., Kumar S., Howley P. M. Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9557–9562. doi: 10.1073/pnas.96.17.9557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Ohta T., Buiting K., Kokkonen H., McCandless S., Heeger S., Leisti H., Driscoll D. J., Cassidy S. B., Horsthemke B., Nicholls R. D. Molecular mechanism of angelman syndrome in two large families involves an imprinting mutation. Am J Hum Genet. 1999 Feb;64(2):385–396. doi: 10.1086/302232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Prasad C., Wagstaff J. Genotype and phenotype in Angelman syndrome caused by paternal UPD 15. Am J Med Genet. 1997 Jun 13;70(3):328–329. doi: 10.1002/(sici)1096-8628(19970613)70:3<328::aid-ajmg21>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  61. Razin A., Cedar H. DNA methylation and genomic imprinting. Cell. 1994 May 20;77(4):473–476. doi: 10.1016/0092-8674(94)90208-9. [DOI] [PubMed] [Google Scholar]
  62. Reis A., Dittrich B., Greger V., Buiting K., Lalande M., Gillessen-Kaesbach G., Anvret M., Horsthemke B. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet. 1994 May;54(5):741–747. [PMC free article] [PubMed] [Google Scholar]
  63. Robinson W. P., Wagstaff J., Bernasconi F., Baccichetti C., Artifoni L., Franzoni E., Suslak L., Shih L. Y., Aviv H., Schinzel A. A. Uniparental disomy explains the occurrence of the Angelman or Prader-Willi syndrome in patients with an additional small inv dup(15) chromosome. J Med Genet. 1993 Sep;30(9):756–760. doi: 10.1136/jmg.30.9.756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Rougeulle C., Cardoso C., Fontés M., Colleaux L., Lalande M. An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript. Nat Genet. 1998 May;19(1):15–16. doi: 10.1038/ng0598-15. [DOI] [PubMed] [Google Scholar]
  65. Rougeulle C., Glatt H., Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet. 1997 Sep;17(1):14–15. doi: 10.1038/ng0997-14. [DOI] [PubMed] [Google Scholar]
  66. Russo S., Cogliati F., Viri M., Cavalleri F., Selicorni A., Turolla L., Belli S., Romeo A., Larizza L. Novel mutations of ubiquitin protein ligase 3A gene in Italian patients with Angelman syndrome. Hum Mutat. 2000 Apr;15(4):387–387. doi: 10.1002/(SICI)1098-1004(200004)15:4<387::AID-HUMU25>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  67. Saitoh S., Buiting K., Cassidy S. B., Conroy J. M., Driscoll D. J., Gabriel J. M., Gillessen-Kaesbach G., Glenn C. C., Greenswag L. R., Horsthemke B. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation. Am J Med Genet. 1997 Jan 20;68(2):195–206. [PubMed] [Google Scholar]
  68. Saitoh S., Harada N., Jinno Y., Hashimoto K., Imaizumi K., Kuroki Y., Fukushima Y., Sugimoto T., Renedo M., Wagstaff J. Molecular and clinical study of 61 Angelman syndrome patients. Am J Med Genet. 1994 Aug 15;52(2):158–163. doi: 10.1002/ajmg.1320520207. [DOI] [PubMed] [Google Scholar]
  69. Saitoh S., Wada T., Kuno T., Kim K. C., Ohashi H., Hashimoto K., Niikawa N. Clinical characteristics of Angelman syndrome patients with a non-IC-deleted imprinting mutation. Clin Genet. 1999 Apr;55(4):277–278. doi: 10.1034/j.1399-0004.1999.550411.x. [DOI] [PubMed] [Google Scholar]
  70. Smeets D. F., Hamel B. C., Nelen M. R., Smeets H. J., Bollen J. H., Smits A. P., Ropers H. H., van Oost B. A. Prader-Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med. 1992 Mar 19;326(12):807–811. doi: 10.1056/NEJM199203193261206. [DOI] [PubMed] [Google Scholar]
  71. Smith A., Deng Z. M., Beran R., Woodage T., Trent R. J. Familial unbalanced translocation t(8;15)(p23.3;q11) with uniparental disomy in Angelman syndrome. Hum Genet. 1994 Apr;93(4):471–473. doi: 10.1007/BF00201679. [DOI] [PubMed] [Google Scholar]
  72. Smith A., Marks R., Haan E., Dixon J., Trent R. J. Clinical features in four patients with Angelman syndrome resulting from paternal uniparental disomy. J Med Genet. 1997 May;34(5):426–429. doi: 10.1136/jmg.34.5.426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Smith A., Robson L., Buchholz B. Normal growth in Angelman syndrome due to paternal UPD. Clin Genet. 1998 Mar;53(3):223–225. doi: 10.1111/j.1399-0004.1998.tb02682.x. [DOI] [PubMed] [Google Scholar]
  74. Smith A., Wiles C., Haan E., McGill J., Wallace G., Dixon J., Selby R., Colley A., Marks R., Trent R. J. Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion. J Med Genet. 1996 Feb;33(2):107–112. doi: 10.1136/jmg.33.2.107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Spritz R. A., Bailin T., Nicholls R. D., Lee S. T., Park S. K., Mascari M. J., Butler M. G. Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. Am J Med Genet. 1997 Jul 11;71(1):57–62. doi: 10.1002/(sici)1096-8628(19970711)71:1<57::aid-ajmg11>3.0.co;2-u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Sutcliffe J. S., Nakao M., Christian S., Orstavik K. H., Tommerup N., Ledbetter D. H., Beaudet A. L. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet. 1994 Sep;8(1):52–58. doi: 10.1038/ng0994-52. [DOI] [PubMed] [Google Scholar]
  77. Talis A. L., Huibregtse J. M., Howley P. M. The role of E6AP in the regulation of p53 protein levels in human papillomavirus (HPV)-positive and HPV-negative cells. J Biol Chem. 1998 Mar 13;273(11):6439–6445. doi: 10.1074/jbc.273.11.6439. [DOI] [PubMed] [Google Scholar]
  78. Tilghman S. M. The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell. 1999 Jan 22;96(2):185–193. doi: 10.1016/s0092-8674(00)80559-0. [DOI] [PubMed] [Google Scholar]
  79. Tonk V., Schultz R. A., Christian S. L., Kubota T., Ledbetter D. H., Wilson G. N. Robertsonian (15q;15q) translocation in a child with Angelman syndrome: evidence of uniparental disomy. Am J Med Genet. 1996 Dec 30;66(4):426–428. doi: 10.1002/(SICI)1096-8628(19961230)66:4<426::AID-AJMG7>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  80. Vu T. H., Hoffman A. R. Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat Genet. 1997 Sep;17(1):12–13. doi: 10.1038/ng0997-12. [DOI] [PubMed] [Google Scholar]
  81. Watson P., Black G., Ramsden S., Barrow M., Super M., Kerr B., Clayton-Smith J. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet. 2001 Apr;38(4):224–228. doi: 10.1136/jmg.38.4.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Williams C. A., Angelman H., Clayton-Smith J., Driscoll D. J., Hendrickson J. E., Knoll J. H., Magenis R. E., Schinzel A., Wagstaff J., Whidden E. M. Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am J Med Genet. 1995 Mar 27;56(2):237–238. doi: 10.1002/ajmg.1320560224. [DOI] [PubMed] [Google Scholar]
  83. Williams C. A., Lossie A., Driscoll D., R.C. Phillips Unit Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet. 2001 Jun 1;101(1):59–64. doi: 10.1002/ajmg.1316. [DOI] [PubMed] [Google Scholar]
  84. van den Ouweland A. M., Bakker P. L., Halley D. J., Catsman-Berrevoets C. E. Angelman syndrome: AS phenotype correlated with specific EEG pattern may result in a high detection rate of mutations in the UBE3A gene. J Med Genet. 1999 Sep;36(9):723–724. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES