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Molecular detection of microscopic and submicroscopic deletions associated with Miller-Dieker syndrome
P vanTuinen1, W B Dobyns, D C Rich
1Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
Abstract:
Miller-Dieker syndrome (MDS), a disorder manifesting the severe brain malformation lissencephaly ("smooth brain"), is caused, in the majority of cases, by a chromosomal microdeletion of the distal short arm of chromosome 17. Using human chromosome 17-specific DNA probes, we have begun a molecular dissection of the critical region for MDS. To localize cloned DNA sequences to the MDS critical region, a human-rodent somatic cell hybrid panel was constructed which includes hybrids containing the abnormal chromosome 17 from three MDS patients with deletions of various sizes. Three genes (myosin heavy chain 2, tumor antigen p53, and RNA polymerase II) previously mapped to 17p were excluded from the MDS deletion region and therefore are unlikely to play a role in its pathogenesis. In contrast, three highly polymorphic anonymous probes, YNZ22.1 (D17S5), YNH37.3 (D17S28), and 144-D6 (D17S34), were deleted in each of four patients with visible deletions, including one with a ring chromosome 17 that is deleted for a portion of the single telomeric prometaphase subband p13.3. In two MDS patients with normal chromosomes, a combination of somatic cell hybrid, RFLP, and densitometric studies demonstrated deletion for YNZ22.1 and YNH37.3 in the paternally derived 17's of both patients, one of whom is also deleted for 144-D6. The results indicate that MDS can be caused by submicroscopic deletion and raises the possibility that all MDS patients will prove to have deletions at a molecular level. The two probes lie within a critical region of less than 3,000 kb and constitute potential starting points in the isolation of genes implicated in the severe brain maldevelopment in MDS.
Insights
Miller-Dieker syndrome (MDS) is linked to deletions on chromosome 17. Researchers identified specific DNA probes within a critical region, suggesting submicroscopic deletions cause this brain malformation.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Miller-Dieker syndrome (MDS) is a severe congenital disorder characterized by lissencephaly (smooth brain).
- MDS is primarily caused by microdeletions on the short arm of chromosome 17 (17p).
Purpose of the Study:
- To molecularly dissect the critical deletion region in Miller-Dieker syndrome on chromosome 17.
- To identify DNA sequences and genes involved in the pathogenesis of MDS.
Main Methods:
- Construction of a human-rodent somatic cell hybrid panel with chromosome 17 abnormalities from MDS patients.
- Utilized human chromosome 17-specific DNA probes to map deletions.
- Employed RFLP (Restriction Fragment Length Polymorphism) and densitometric studies.
Main Results:
- Three known genes (myosin heavy chain 2, p53, RNA polymerase II) were excluded from the MDS deletion region.
- Three polymorphic DNA probes (YNZ22.1, YNH37.3, 144-D6) were deleted in MDS patients with visible deletions.
- Submicroscopic deletions of YNZ22.1 and YNH37.3 were identified in MDS patients with apparently normal chromosomes, indicating deletions at a molecular level.
Conclusions:
- MDS can result from submicroscopic deletions on chromosome 17p.
- The identified probes YNZ22.1 and YNH37.3 are located within a critical region of <3,000 kb, serving as starting points for gene isolation.
- These findings suggest all MDS cases may involve molecular-level deletions, crucial for understanding MDS pathogenesis.