Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Apr;72(4):918-30.
doi: 10.1086/374320. Epub 2003 Mar 5.

Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3

Carlos Cardoso  1 , Richard J Leventer, Heather L Ward, Kazuhito Toyo-Oka, June Chung, Alyssa Gross, Christa L Martin, Judith Allanson, Daniela T Pilz, Ann H Olney, Osvaldo M Mutchinick, Shinji Hirotsune, Anthony Wynshaw-Boris, William B Dobyns, David H Ledbetter
Affiliations

Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3

Carlos Cardoso et al. Am J Hum Genet. 2003 Apr.

Abstract

Deletions of 17p13.3, including the LIS1 gene, result in the brain malformation lissencephaly, which is characterized by reduced gyration and cortical thickening; however, the phenotype can vary from isolated lissencephaly sequence (ILS) to Miller-Dieker syndrome (MDS). At the clinical level, these two phenotypes can be differentiated by the presence of significant dysmorphic facial features and a more severe grade of lissencephaly in MDS. Previous work has suggested that children with MDS have a larger deletion than those with ILS, but the precise boundaries of the MDS critical region and causative genes other than LIS1 have never been fully determined. We have completed a physical and transcriptional map of the 17p13.3 region from LIS1 to the telomere. Using fluorescence in situ hybridization, we have mapped the deletion size in 19 children with ILS, 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. We show that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, we have identified eight genes that are consistently deleted in patients classified as having MDS. In addition, deletion of the genes CRK and 14-3-3 epsilon delineates patients with the most severe lissencephaly grade. On the basis of recent functional data and the creation of a mouse model suggesting a role for 14-3-3 epsilon in cortical development, we suggest that deletion of one or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with MDS.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Detailed phenotypic analysis of patients with deletions of 17p13.3, showing increasing severity of brain and face changes with larger deletions extending closer to the 17p telomere. LP95-108 has typical ILS with normal facial appearance (A) and LIS grade 3 with a posterior > anterior gradient (B) associated with a small submicroscopic deletion. LP99-086 has ILS with facial changes intermediate between typical ILS and MDS (C) and LIS grade 3 with a posterior > anterior gradient (D). LP82-002 (E and F) and LR01-167 (G and H) have consensus MDS (E and G) and severe LIS grade 1 (F and H) with no visible gradient. Both the brain and face abnormalities are more severe than in the patients with ILS shown (A–D). Normal T1 and T2 axial images are shown for comparison (I and J). The face and brain abnormalities are more subtle in subjects with deletions that do not include the LIS1 gene. DR01-001 has a mildly dysmorphic facial appearance not specific for MDS (K) and mild frontal lobe hypoplasia without LIS (L).
Figure 2
Figure 2
Physical and transcriptional map of the interval from D17S1845 to the telomere. A, The chromosomal orientation of the BAC/PAC contig covering the most distal 2.8 Mb of chromosome 17 in the region p13.3 is indicated. STS markers, genes, and BAC ends used for mapping are depicted by vertical lines at the top of the figure. A gray or red circle signifies the presence of an STS, a gene, or a BAC end on an individual PAC or BAC clone. All PAC clones are underlined, and BAC clones used in FISH analysis are indicated in red. The broken line indicates the gap between the main contig and the telomeric minicontig. Known genes mapped previously in this region are noted in blue, and the direction of transcription is indicated by an arrow. A pseudogene is denoted by a black box. The cDNA clones corresponding to unknown genes are noted in green. All known and new genes are placed exactly below the genomic clones that contain them. B, Schematic representation of deletions of the 17p13.3 region identified in patients with ILS, MDS, or other phenotypes without LIS. The solid lines below the map represent nondeleted genomic BAC/PAC clones. The dotted lines represent deletions associated with the patient number listed above. For patients with ILS or MDS, the dashed line indicates the largest deletion identified in each group of patients. The telomeric boundaries of 17p13.3 deletion of hybrids SG2, BR8, DB, CA2, and KCB4 are indicated by orange circles.
Figure 3
Figure 3
Extent of deletion in 12 patients with MDS, 18 patients with ILS, and 4 patients without LIS. Black boxes denote the presence of the probe on both copies of chromosome 17, and white boxes denote the presence of the probe on only one chromosome 17. Gray boxes denote a partial deletion of the probe on one chromosome 17. na = Data not available. BAC ID numbers (boldface) and gene symbols (italics) are listed across the top of the figure from centromere (left) to telomere (right).
Figure 4
Figure 4
Three-color FISH analysis showing the variability of the deletions of the 17p13.3 region. Three probes—PAC95H6 (red), BAC818O24 (green), and BAC68F18 (magenta)—from the 17p subtelomeric region were used in these FISH experiments to size the deletion of the 17p13.3 region in various patients (B, C, and D) compared with a normal control (A). B, FISH on patient (LP99-086) who has ILS (fig. 1C and 1D) showed the absence of PAC95H6 in red (containing the LIS1 gene). C, In patient LR01-167, who has MDS (fig. 1G and 1H), there is absence of signal of all three probes on one chromosome 17. D, Patient DR01-001 does not have all typical MDS facial features or LIS, but does have an abnormal brain MRI (frontal lobe hypoplasia and partial agenesis of the corpus callosum) (fig. 1K and 1L). Her FISH study shows the presence of PAC95H6 on both chromosome 17s and absence of the probes BAC818O24 and BAC68F18 from one chromosome 17.
Figure 5
Figure 5
Extent of deletion in the telomeric MDS critical region. PCR analysis was performed on somatic cell hybrid cell lines derived from lymphoblasts of three patients with ILS—SG2 (LP90-017), BR8 (LP87-001), and DB (LP86-003)—and from two patients with MDS—CA2 (LP82-002) and KCB4 (LP84-001)—whose deletion breakpoints have been characterized by FISH analysis. Primers used specially amplified all 10 human genes (see the “Subjects and Methods” section) that extend from the centromere (SERPINF1) to telomere (ABR) that are present within the telomeric MDS critical region. DNAs from hamster, mouse, and human were used in these experiments to show the specificity of the primers.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

Electronic-Database Information

    1. CEPH-Généthon Database, http://www.cephb.fr/
    1. GenBank, http://www.ncbi.nlm.nih.gov/entrez/, (for RPCI4-765O05 [accession no. AL137038], RPCI5-59D14 [accession no. AC006435], RPCI5-1029F21 [accession no. AC015853], RPCI5-1037N22 [accession no. AL450226], RPCI5-1127L24 [accession no. AC008087], RPCI11-4F24 [accession no. AC007873], RPCI11-22G12 [accession no. AC016292], RPCI11-74E22 [accession no. AC005696], RPCI11-107N19 [accession no. AC006405], RPCI11-135N5 [accession no. AC015799], RPCI11-216P6 [accession no. AC015884], RPCI11-356I18 [accession no. AC036164], RPCI11-380H7 [accession no. AC021705], RPCI11-411G7 [accession no. AC027455], RPCI11-433M14 [accession no. AC068936], RPCI11-667K14 [accession no. AC090617], RPCI11-676J12 [accession no. AC087392], RPCI11-818O24 [accession no. AC032044], CTB-11O23 [accession no. AC002316], BAC407I21 [accession no. AF322450], CTB-145P4 [accession no. AC002093], CTD-2326F1 [accession no. AC109339], CTD-2348K1 [accession no. AC108004], CTD-2507J6 [accession no. AC107911], CTD-2545H1 [accession no. AC099684], CTD-2573J8 [accession no. AC108006], CTD-3086F13 [accession no. AC099721] and yRM2111 (17pTEL) [accession no. AF240580], RPCI23-78H4 [accession no. AL669897], RPCI23-190H20 [accession no. AL663094], RPCI11-305G1 [accession no. AC032038], RPCI11-713H12 [accession no. AC025518], NUDEL [accession no. NM_030808], profilin1 [accession no. NM_005022], KIAA0664 [accession no. XM_03478], LIS1 [accession no. XM_034770], MNT [accession no. XM_012601], SRR [accession no. NM_021947], KIAA0397 [accession no. AB007857], C17orf31 [or KIAA0732] [accession no. XM_029470], KIAA1401 [accession no. AB037822], HIC1 [accession no. NM_006497], DPH2L [accession no. NM_001383], RPA1 [accession no. NM_002945], SERPINF2 [accession no. NM_000934], SERPINF1 [accession no. NM_002615], KIAA1936 [accession no. XM_056082], PRP8 [accession no. XM_028335], RILP [accession no. NM_031430], SREC [accession no. XM_008489], PITPN-α [accession no. NM_006224], SKIP [accession no. NM_016532], MYO1C [accession no. XM_028385], CRK III [accession no. NM_005206 and NM_016823], 14-3-3ε [accession no. NM_006761], ABR [accession no. NM_021962 and NM_001092], TIMM22 [accession no. XM_033715], NXN [accession no. XM_033714], HC90 [accession no. AF177344], CGI-150 [accession no. NM_016080], ELP [accession no. AF229804], HC56 [accession no. AF177341], FLJ22282 [accession no. NM_024792], FLJ32270 [accession no. AK056832], FLJ10979 [accession no. NM_018289], FLJ31761 [accession no. AK056323], RPH3AL [accession no. NM_006987], and DOC2B [accession no. NM_003585])
    1. HUGO chromosome 17, http://gdbwww.gdb.org/hugo/chr17/
    1. Lissencephaly Network, http://www.lissencephaly.org
    1. NCBI UniGene, http://www.ncbi.nlm.nih.gov/UniGene/

References

    1. Adachi H, Tsujimoto M (2002) Characterization of human gene encoding scavenger receptor expressed by endothelial cells (SREC) and its regulation by a novel transcription factor, endothelial zinc finger protein-2 (EZF-2). J Biol Chem 277:24014–24021 - PubMed
    1. Cardoso C, Leventer RJ, Matsumoto N, Kuc JA, Ramocki MB, Mewborn SK, Dudlicek LL, May LF, Mills PL, Das S, Pilz DT, Dobyns WB, Ledbetter DH (2000) The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. Hum Mol Genet 9:3019–3028 - PubMed
    1. Chong SS, Tanigami A, Roschke AV, Ledbetter DH (1996) 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. Genome Res 6:735–741 - PubMed
    1. Chong SS, Pack SD, Roschke AV, Tanigami A, Carrozzo R, Smith AC, Dobyns WB, Ledbetter DH. (1997) A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet 6:147–155 - PubMed
    1. Christian, SL, Fantes JA, Mewborn SK, Huang B, Ledbetter DH (1999) Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11–q13). Hum Mol Genet 8:1025–1037 - PubMed

Publication types

Substances

Associated data