The spectrum of mutations in UBE3A causing Angelman syndrome

被引:118
作者
Fang, P
Lev-Lehman, E
Tsai, TF
Matsuura, T
Benton, CS
Sutcliffe, JS
Christian, SL
Kubota, T
Halley, DJ
Meijers-Heijboer, H
Langlois, S
Graham, JM
Beuten, J
Willems, PJ
Ledbetter, DH
Beaudet, AL [1 ]
机构
[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[2] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA
[3] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA
[4] Shinshu Univ, Dept Hyg & Med Genet, Nagano, Japan
[5] Erasmus Univ Hosp, Dept Clin Genet, Rotterdam, Netherlands
[6] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 1M9, Canada
[7] Cedars Sinai Med Ctr, Ctr Med Genet Birth Defects, Los Angeles, CA 90048 USA
[8] Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium
[9] Univ Antwerp, Dept Neurogenet, B-2020 Antwerp, Belgium
关键词
D O I
10.1093/hmg/8.1.129
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction, AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase, The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype, Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8, In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.
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页码:129 / 135
页数:7
相关论文
共 33 条
  • [1] Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons
    Albrecht, U
    Sutcliffe, JS
    Cattanach, BM
    Beechey, CV
    Armstrong, D
    Eichele, G
    Beaudet, AL
    [J]. NATURE GENETICS, 1997, 17 (01) : 75 - 78
  • [2] Antonarakis SE, 1998, HUM MUTAT, V11, P1
  • [3] The proteasome:: Paradigm of a self-compartmentalizing protease
    Baumeister, W
    Walz, J
    Zühl, F
    Seemuller, E
    [J]. CELL, 1998, 92 (03) : 367 - 380
  • [4] Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome:: Implications for imprint-switch models, genetic counseling, and prenatal diagnosis
    Buiting, K
    Dittrich, B
    Gross, S
    Lich, C
    Färber, C
    Buchholz, T
    Smith, E
    Reis, A
    Bürger, J
    Nöthen, MM
    Barth-Witte, U
    Janssen, B
    Abeliovich, D
    Lerer, I
    van den Ouweland, AMW
    Halley, DJJ
    Schrander-Stumpel, C
    Smeets, H
    Meinecke, P
    Malcolm, S
    Gardner, A
    Lalande, M
    Nicholls, RD
    Friend, K
    Schulze, A
    Matthijs, G
    Kokkonen, H
    Hilbert, P
    Van Maldergem, L
    Glover, G
    Carbonell, P
    Willems, P
    Gillessen-Kaesbach, G
    Horsthemke, B
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 63 (01) : 170 - 180
  • [5] The ubiquitin-proteasome pathway: The complexity and myriad functions of proteins death
    Ciechanover, A
    Schwartz, AL
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (06) : 2727 - 2730
  • [6] UBE3A "mutations" in two unrelated and phenotypically different Angelman syndrome patients
    Fung, DCY
    Yu, B
    Cheong, KF
    Smith, A
    Trent, RJ
    [J]. HUMAN GENETICS, 1998, 102 (04) : 487 - 492
  • [7] Ubiquitin-dependent protein degradation
    Hochstrasser, M
    [J]. ANNUAL REVIEW OF GENETICS, 1996, 30 : 405 - 439
  • [8] Protein degradation or regulation: Ub the judge
    Hochstrasser, M
    [J]. CELL, 1996, 84 (06) : 813 - 815
  • [9] Horsthemke B, 1997, HUM MUTAT, V10, P329, DOI 10.1002/(SICI)1098-1004(1997)10:5<329::AID-HUMU1>3.0.CO
  • [10] 2-A