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PMID: 12621583 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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.

American journal of human genetics ·Vol. 72 ·No. 4 ·2003-04-00 ·Pages 918-30

Cardoso C, Leventer RJ, Ward HL, Toyo-Oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirotsune S, Wynshaw-Boris A, Dobyns WB, Ledbetter DH

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.

MeSH Terms

1-Alkyl-2-acetylglycerophosphocholine Esterase Abnormalities, Multiple/genetics Base Sequence Chromosome Deletion Chromosomes, Human, Pair 17 Congenital Abnormalities/genetics DNA Primers Female Genotype Humans Infant Male Microtubule-Associated Proteins/genetics Molecular Sequence Data Phenotype Retrospective Studies Syndrome Telomere/genetics Transcription, Genetic

Chemicals

DNA Primers Microtubule-Associated Proteins 1-Alkyl-2-acetylglycerophosphocholine Esterase PAFAH1B1 protein, human Pafah1b1 protein, mouse

Authors & Affiliations

15 authors, click to expand affiliations / ORCID

Cardoso Carlos

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.

Leventer Richard J

Ward Heather L

Toyo-Oka Kazuhito

Chung June

Gross Alyssa

Martin Christa L

Allanson Judith

Pilz Daniela T

Olney Ann H

Mutchinick Osvaldo M

Hirotsune Shinji

Wynshaw-Boris Anthony

Dobyns William B

Ledbetter David H

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35 references, click to expand

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Article Info

Journal

American journal of human genetics

Abbr.

Am J Hum Genet

ISSN

0002-9297

DOI

10.1086/374320

Published

2003-04-00

Epub

2003-00-05

Pages

918-30

Language

English

Region

United States

NLM ID

0370475

PMCID

PMC1180354

Subset

Grants

NINDS NIH HHS · P01 NS039404 · United States

NINDS NIH HHS · P01 NS39404 · United States

NICHD NIH HHS · R01 HD36715-03 · United States

Databases

GENBANK

AB007857, AB037822, AC002093, AC002316, AC005696, AC006405, AC006435, AC007873, AC008087, AC015799, AC015853, AC015884, AC016292, AC021705, AC025518, AC027455, AC032038, AC032044, AC036164, AC068936, AC087392, AC090617, AC099684, AC099721, AC107911, AC108004, AC108006, AC109339, AF177341, AF177344, AF229804, AF240580, AF322450, AK056323, AK056832, AL137038, AL450226, AL663094, AL669897

OMIM

247200, 300121, 601545

RefSeq

NM_000934, NM_001092, NM_001383, NM_002615, NM_002945, NM_003585, NM_005022, NM_005206, NM_006224, NM_006497, NM_006761, NM_006987, NM_016080, NM_016532, NM_016823, NM_018289, NM_021947, NM_021962, NM_024792, NM_030808, NM_031430, XM_008489, XM_012601, XM_028335, XM_028385, XM_029470, XM_033714, XM_033715, XM_034770, XM_056082

External Links

PubMed source DOI: 10.1086/374320 PMC Full Text View journal details

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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.

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