Molecular Dissection of a Contiguous Gene Syndrome: Frequent Submicroscopic Deletions, Evolutionarily Conserved Sequences, and a Hypomethylated "Island" in the Miller-Dieker Chromosome Region

• Published in: Proceedings of the National Academy of Sciences - PNAS 1989-07, Vol.86 (13), p.5136-5140
• Main Authors: Ledbetter, David H., Ledbetter, Susan A., VanTuinen, Peter, Summers, Kim M., Robinson, Terence J., Nakamura, Yusuke, Wolff, Roger, White, Ray, Barker, David F., Wallace, Margaret R., Collins, Francis S., Dobyns, William B.
• Format: Article
• Language: English
• Subjects: 550401 - Genetics- Tracer Techniques; ANIMALS; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; Biological and medical sciences; BIOLOGICAL EVOLUTION; BIOLOGICAL MARKERS; Blotting, Southern; Brain - abnormalities; CHEMICAL REACTIONS; CHROMOSOMAL ABERRATIONS; Chromosome Deletion; Chromosome Mapping; CHROMOSOMES; Chromosomes, Human, Pair 17; Cosmids; DAYS LIVING RADIOISOTOPES; DISEASES; DNA; DNA HYBRIDIZATION; DNA probes; DNA SEQUENCING; ELECTROPHORESIS; Face - abnormalities; Gels; Genes; Genetic loci; GENETIC MAPPING; HEREDITARY DISEASES; HETEROCHROMOSOMES; Human chromosomes; Humans; Hybrid cells; Hybridity; HYBRIDIZATION; ISOTOPES; KARYOTYPE; LIGHT NUCLEI; Malformations of the nervous system; MAMMALS; MAN; MAPPING; Medical sciences; METHYLATION; MICE; Minisatellite repeats; MOLECULAR BIOLOGY; MUTATIONS; Neurology; NUCLEI; NUCLEIC ACIDS; ODD-ODD NUCLEI; ORGANIC COMPOUNDS; PHOSPHORUS 32; PHOSPHORUS ISOTOPES; PRIMATES; RADIOISOTOPES; Restriction Mapping; RFLPS; RODENTS; STRUCTURAL CHEMICAL ANALYSIS; Syndrome; VERTEBRATES
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.86.13.5136

The Miller-Dieker syndrome (MDS), composed of characteristic facial abnormalities and a severe neuronal migration disorder affecting the cerebral cortex, is caused by visible or submicroscopic deletions of chromosome band 17p13. Twelve anonymous DNA markers were tested against a panel of somatic cell hybrids containing 17p deletions from seven MDS patients. All patients, including three with normal karyotypes, are deleted for a variable set of 5-12 markers. Two highly polymorphic VNTR (variable number of tandem repeats) probes, YNZ22 and YNH37, are codeleted in all patients tested and make molecular diagnosis for this disorder feasible. By pulsed-field gel electrophoresis, YNZ22 and YNH37 were shown to be within 30 kilobases (kb) of each other. Cosmid clones containing both VNTR sequences were identified, and restriction mapping showed them to be 100 kb were completely deleted in all patients, providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region, indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. The conserved sequences were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 centimorgans, into the 17p telomere region.