Miller-Dieker syndrome (MDS) is s contiguous gene syndrome comprised of a severe neuronal migration disorder producing type I lissencephaly (smooth brain, argyria), characteristic dysmorphic features, and other congenital abnormalities. It is caused by a cytogenetic microdeletion in about half of cases, while the other half have recently been shown by us to have submicroscopic deletions detected by anonymous DNA probes. MDS thus offers a model system for the reverse genetics cloning of genes involved in the pathogenesis of a complex disease phenotype, and a more basic understanding of mechanisms of cytogenetic disorders and normal corticogenesis. Specific goals of the project include: 1) improved diagnostic ability in MDS by identification of new DNA probes in the critical region, additional RFLPs, and development of rapid RFLP analysis by the polymerase chain reaction (PCR). We will also determine whether patients with isolated lissencephaly syndrome (ILS), without the dysmorphic features of MDS, also have deletions or other alterations of a locus on 17p. 2) Study of mechanisms of chromosome rearrangement by determination of parental origin of rearrangements, pulsed-field detection of deletion and translocation breakpoints, followed by strategies to clone and sequence the breakpoint junctions. 3) Search for candidate genes by identification of evolutionarily conserved sequences and HTF islands, followed by search for RNA transcripts and identification of corresponding cDNA clones. 4) Contribute to human genome project and comparative mapping in man and mouse. A high- resolution regional mapping panel for 17p is being developed by addition of new patient breakpoints isolated in somatic cell hybrids, a long-range restriction map is being developed by pulsed- field gel analysis, and mapping in the mouse is being conducted by somatic cell hybrid techniques and by analysis of interspecific backcrosses between mus spretus and mus domesticus. We will determine whether MDS probes map close to known mouse neurological mutations, which may provide an animal model for MDS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD020619-04
Application #
3318897
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1986-07-01
Project End
1994-03-31
Budget Start
1989-07-01
Budget End
1990-03-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Ben-Arie, N; Lancet, D; Taylor, C et al. (1994) Olfactory receptor gene cluster on human chromosome 17: possible duplication of an ancestral receptor repertoire. Hum Mol Genet 3:229-35
Sutcliffe, J S; Nakao, M; Christian, S et al. (1994) Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet 8:52-8
Nakao, M; Sutcliffe, J S; Durtschi, B et al. (1994) Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum Mol Genet 3:309-15
Dobyns, W B; Reiner, O; Carrozzo, R et al. (1993) Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA 270:2838-42
Robinson, W P; Bernasconi, F; Mutirangura, A et al. (1993) Nondisjunction of chromosome 15: origin and recombination. Am J Hum Genet 53:740-51
Mutirangura, A; Greenberg, F; Butler, M G et al. (1993) 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 2:143-51
Mutirangura, A; Jayakumar, A; Sutcliffe, J S et al. (1993) A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11-q13) and refined localization of the SNRPN gene. Genomics 18:546-52
Ledbetter, S A; Kuwano, A; Dobyns, W B et al. (1992) Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am J Hum Genet 50:182-9
Ledbetter, D H (1992) Minireview: cryptic translocations and telomere integrity. Am J Hum Genet 51:451-6
Dobyns, W B; Elias, E R; Newlin, A C et al. (1992) Causal heterogeneity in isolated lissencephaly. Neurology 42:1375-88

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