Mark Rabin

An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma

The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10–15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.

Regional location of α1-antichymotrypsin and α1-antitrypsin genes on human chromosome 14

The human protease inhibitor genes α1 antitrypsin (α1-PI) and α1-antichymotrypsin (α1-ACT) are acute-phase proteins which are induced in response to inflammation. These inhibitors function to limit the activity of serine proteases in vivo. α1-PI acts as an inhibitor of neutrophil elastase to protect the elastin fibers of the lung. Genetic deficiencies of α1-PI result in development of chronic pulmonary emphysema. The physiologic role of α1-ACT has not been clearly defined, but it also appears to function in the maintenance of protease-protease inhibitor equilibrium in the lung. Nucleic acid and protein sequence homologies detected between α1-PI and α1 t-ACT suggested an evolutionary relationship. Gene mapping experiments were performed to determine if these protease inhibitor genes reside at the same chromosomal locus in man. In situ hybridization data demonstrate that both α1-PI and α1-ACT map to the same region, q31–q32.3, on chromosome 14.

Homeo box genes in murine development.

Considerable information has accumulated on mouse homeo box gene organization and expression. Homeo box genes are expressed in a wide variety of tissues, developmental stages, and cell lines. How can this be interpreted in view of the relationship of these genes to Drosophila morphogenetic loci? One view is that homeo box genes control determinative decisions by modulating transcription of as yet unidentified target genes. Proponents of this view are faced with two tasks: to identify developmental processes that are controlled by homeo box genes, and to identify the target genes that mediate this control. Such target genes might be identified on the basis of in vitro homeo domain-DNA interactions. Candidate morphogenetic processes might be identified on the basis of the observed patterns of homeo box gene expression. It must be stressed that finding expression in a given tissue in no way demonstrates that the expression is necessary for the determination of that tissue. The role of Drosophila homeo box genes in determinative decisions is based upon analysis of mutants to demonstrate that the pattern of homeo box gene expression determines the morphogenetic outcome. To test whether the expression of a mouse homeo box gene is involved in a determinative decision, one must disrupt the normal pattern of expression of that gene and observe the resulting morphogenetic effect. In mouse this can be approached by looking for allelism with known morphogenetic loci, by isolating mutants in homeo box genes through large-scale mutagenesis screens, or by introducing altered homeo box genes into transgenic mice. One of the most intriguing possibilities is that homeo box genes are involved in regional specification along the anteroposterior axis. In situ hybridization and Northern blot analysis have demonstrated that at least four different homeo box genes display distinct regional patterns of expression along the anteroposterior axis of the developing CNS. The expression of each of these genes has a unique anterior boundary from which expression extends posteriorly within the CNS. Hox 1.5 expression has an anterior boundary within the hindbrain just posterior to the pontine flexure. The anterior boundary of Hox 2.1 expression lies more posteriorly within the medulla of the hindbrain. Weak expression of Hox 2.5 is detected in the spinal cord just posterior to the first cervical vertebra, and maximal expression is found posterior to the second cervical vertebra.(ABSTRACT TRUNCATED AT 400 WORDS)

Proximity of thyroglobulin and c-myc genes on human chromosome 8.

The human thyroglobulin structural gene (TG) was mapped to the long arm of chromosome 8 by blot hydridization of a TG cDNA probe to DNA from 21 human × mouse somatic cell hybrids containing overlapping subsets of human chromosomes. In situ hybridization of the TG probe to metaphase chromosomes from a karyotypically normal human lymphoblastoid cell line, JS, localized the TG gene to within the region 8q23 → q24.3. Thus, the TG and c-myc genes map to the same chromosome band in normal human cells. In a human colon carcinoma cell line (COLO 320 DM) which contains amplified c-myc, the TG gene is not amplified and hence it lies outside the amplification domain.

Chromosomal assignment of gene encoding the largest subunit of RNA polymerase II in the mouse

The gene encoding the largest subunit of RNA polymerase II was mapped to mouse chromosome 11 by Southern blotting analysis of mouse-Chinese hamster somatic cell hybrids and by in situ hybridization. This assignment extends the previously defined homology between mouse chromosome 11 and human chromosome 17.

Comparative Genetic Analysis of Homeobox Genes in Mouse and Man

Homeobox sequences in insects have been described as repetitive elements in homeotic genes (McGinnis et al., 1984a). They have also been found in other genes that have developmental functions. The homeobox sequences are conserved in many animal groups across the protostome and deuterostome lineages of evolutionary ascent. Highly conserved homeobox sequences have been described in numerous vertebrates, including amphibians and mammals (McGinnis et al., 1984b). We have been especially concerned with homeobox sequences in the mouse and in man (McGinnis et al., 1984c). It is now certain that the homeobox sequences code domains within functional genes in vertebrates, on the basis of their expression in polyadenylated RNA transcripts (Hart et al., 1985). Moreover, the tissue-specific expression and temporal patterns of expression are both consistent with a developmental role (Awgulewitsch et al., 1986).