Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome

被引:205
作者
LoNigro, C
Chong, SS
Smith, ACM
Dobyns, WB
Carrozzo, R
Ledbetter, DH
机构
[1] HOSP SAN RAFFAELE,MOL GENET LAB,I-20132 MILAN,ITALY
[2] HOSP SAN RAFFAELE,SERV GENET MED,I-20132 MILAN,ITALY
[3] TELETHON INST GENET & MED,MILAN,ITALY
[4] NIH,NATL CTR HUMAN GENOME RES,BETHESDA,MD 20892
[5] GEORGETOWN UNIV,MED CTR,DEPT PEDIAT,WASHINGTON,DC 20007
[6] UNIV MINNESOTA,SCH MED,DEPT NEUROL,DIV PEDIAT NEUROL,MINNEAPOLIS,MN 55455
[7] UNIV MINNESOTA,SCH MED,DEPT PEDIAT,MINNEAPOLIS,MN 55455
关键词
D O I
10.1093/hmg/6.2.157
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
Classical lissencephaly (smooth brain) or generalized agyria-pachygyria is a severe brain malformation which results from an arrest of neuronal migration at 9-13 weeks gestation, It has been observed in several malformation syndromes including Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS), A gene containing P-transducin like repeats, now known as LIS1, was previously mapped to the ILS/MDS chromosome region on 17p13.3. We recently localized the classical lissencephaly critical region to the LISI gene locus by molecular analysis of key ILS and MDS patients, We have now characterized the structure of LISI, which consists of 11 exons, and have searched for the presence of subtle mutations in 19 ILS patients who showed no gross rearrangements of LISI, Single strand conformational polymorphism (SSCP) analysis revealed band-shifts for three patients, each involving a different coding exon, which were not observed in their respective parental DNAs. Sequence analysis identified these de novo mutations as a dA-->dG transition in exon VI at nucleotide 446, a dC-->dT transition in exon VIII at nucleotide 817, and a 22 bp deletion at the exon IX-intron 9 junction from nucleotide 988 to 1002+7, which causes skipping of exon IX in the mature LIS1 transcript, These changes are predicted to result in an H149R amino acid substitution, an R273X premature translation termination, and abolition of amino acids 301-334, in the respective LIS1 proteins. These data thus confirm LIS1 as the gene responsible for classical lissencephaly in ILS and MDS.
引用
收藏
页码:157 / 164
页数:8
相关论文
共 29 条
  • [1] THE SPECTRUM OF LISSENCEPHALY - REPORT OF 10 PATIENTS ANALYZED BY MAGNETIC-RESONANCE-IMAGING
    BARKOVICH, AJ
    KOCH, TK
    CARROL, CL
    [J]. ANNALS OF NEUROLOGY, 1991, 30 (02) : 139 - 146
  • [2] Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly
    Brunelli, S
    Faiella, A
    Capra, V
    Nigro, V
    Simeone, A
    Cama, A
    Boncinelli, E
    [J]. NATURE GENETICS, 1996, 12 (01) : 94 - 96
  • [3] CARSTENS RP, 1991, AM J HUM GENET, V48, P1105
  • [4] CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P56
  • [5] A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3
    Chong, SS
    Pack, SD
    Roschke, AV
    Tanigami, A
    Carrozzo, R
    Smith, ACM
    Dobyns, WB
    Ledbetter, DH
    [J]. HUMAN MOLECULAR GENETICS, 1997, 6 (02) : 147 - 155
  • [6] 14-3-3 epsilon has no homology to LIS1 and lies telomeric to it on chromosome 17p13.3 outside the Miller-Dieker syndrome chromosome region
    Chong, SS
    Tanigami, A
    Roschke, AV
    Ledbetter, DH
    [J]. GENOME RESEARCH, 1996, 6 (08): : 735 - 741
  • [7] Platelet-activating factor produces neuronal growth cone collapse
    Clark, GD
    McNeil, RS
    Bix, GJ
    Swann, JW
    [J]. NEUROREPORT, 1995, 6 (18) : 2569 - 2575
  • [8] DOBYNS WB, 1991, AM J HUM GENET, V48, P584
  • [9] X-linked malformations of neuronal migration
    Dobyns, WB
    Andermann, E
    Andermann, F
    CzapanskyBeilman, D
    Dubeau, F
    Dulac, O
    Guerrini, R
    Hirsch, B
    Ledbetter, DH
    Lee, NS
    Motte, J
    Pinard, JM
    Radtke, RA
    Ross, ME
    Tampieri, D
    Walsh, CA
    Truwit, CL
    [J]. NEUROLOGY, 1996, 47 (02) : 331 - 339
  • [10] CAUSAL HETEROGENEITY IN ISOLATED LISSENCEPHALY
    DOBYNS, WB
    ELIAS, ER
    NEWLIN, AC
    PAGON, RA
    LEDBETTER, DH
    [J]. NEUROLOGY, 1992, 42 (07) : 1375 - 1388