Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3.

Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disorder and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al. 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation.

Ablepharon macrostomia syndrome with associated cutis laxa: possible localization to 18q.

The ablepharon-macrostomia (AMS) and Barber-Say syndromes (BSS) are rare disorders characterized by absence of the eyelids or ectropion, macrostomia, ambiguous genitalia, abnormal ears, rudimentary nipples, and dry, redundant skin. Patients with Barber-Say syndrome also have hypertrichosis. We present a patient with a phenotype similar to AMS who has a complex rearrangement of chromosome 18, involving both an inversion and interstitial deletion. Our patient lacks the typical features of the 18q deletion syndrome. We review AMS and BSS as compared with our patient, and recognize cutis laxa as a feature shared by all. We propose that the gene(s) for this phenotype may lie on chromosome 18 in the region of the deletion or inversion breakpoints.

Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18.

In an effort to identify regions on chromosome 18 that may be critical in the appearance of the Edwards syndrome phenotype, we have analyzed six patients with partial duplication of chromosome 18. Four of the patients have duplications involving the distal half of 18q (18q21.1-qter) and are very mildly affected. The remaining two patients have most of 18q (18q12.1-qter) duplicated, are severely affected, and have been diagnosed with Edwards syndrome. We have employed FISH, using DNA probes from a chromosome 18-specific library, for the precise determination of the duplicated material in each of these patients. The clinical features and the extent of the chromosomal duplication in these patients were compared with four previously reported partial trisomy 18 patients, to identify regions of chromosome 18 that may be responsible for certain clinical features of trisomy 18. The comparative analysis confirmed that there is no single region on 18q that is sufficient to produce the trisomy 18 phenotype and identified two regions on 18q that may work in conjunction to produce the Edwards syndrome phenotype. In addition, correlative analysis indicates that duplication of 18q12.3-q22.1 may be associated with more severe mental retardation in trisomy 18 individuals.

Cytogenetic findings in primary uveal melanoma.

We analyzed cytogenetic abnormalities in 10 cases of primary uveal melanoma. Clonal chromosomal abnormalities were present in nine cases. Chromosome 6 was most commonly affected (seven cases) and included gain of material from 6 and/or loss of material from 6q. Trisomy of chromosome 8 or gain in material from 8q, mostly in the form of an i(8q) resulting in three to five copies of the 8q segment was seen in six cases. Monosomy of chromosome 3 and rearrangements of chromosome 9 were less frequent and were altered in three cases each. Clinical, histopathologic, and cytogenetic abnormalities are correlated.

Detailed genetic and physical map of the 3p chromosome region surrounding the familial renal cell carcinoma chromosome translocation, t(3;8)(p14.2;q24.1).

Extensive studies of loss of heterozygosity of 3p markers in renal cell carcinomas (RCCs) have established that there are at least three regions critical in kidney tumorigenesis, one most likely coincident with the von Hippel-Lindau gene at 3p25.3, one in 3p21 which may also be critical in small cell lung carcinomas, and one in 3p13-p14.2, a region which includes the 3p chromosome translocation break of familial RCC with the t(3;8)(p14.2;q24.1) translocation. A panel of rodent-human hybrids carrying portions of 3p, including a hybrid carrying the derivative 8 (der(8)(8pter-->8q24.1::3p14.2-->3pter)) from the RCC family, have been characterized using 3p anchor probes and cytogenetic methods. This 3p panel was then used to map a large number of genetically mapped probes into seven physical intervals between 3p12 and 3pter defined by the hybrid panel. Markers have been physically, and some genetically, placed relative to the t(3;8) break, such that positional cloning of the break is feasible.

Expression of Fc gamma RII and CD4 receptors by normal human megakaryocytes.

We studied human megakaryocytes to determine if they both expressed and synthesized Fc gamma and CD4 membrane receptors. The strategy employed relied on demonstration of receptor protein and mRNA in megakaryocytes present in freshly made marrow smears, or in megakaryocytes isolated from aspirated normal bone marrow by counterflow centrifugal elutriation. Protein was detected immunochemically, whereas mRNA was detected either by in situ hybridization, or by reverse transcription, polymerase chain reaction (RT-PCR). Using these methods CD4 and Fc gamma RII protein and mRNA were detected in most megakaryocytes. Fc gamma RI and Fc gamma RIII protein was not detected in these cells. Megakaryocytes were also cultured with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the effect of this growth factor on Fc gamma RII expression. As has been noted in cells of the monocyte-macrophage lineage, exposure to rhGM-CSF resulted in a significant increase in the level of megakaryocyte Fc gamma RII mRNA and protein. These observations are significant because they provide a physiologic basis for known viral trophism displayed by megakaryocytes. They are also of interest because they suggest that alternative portals exist for entry of human immunodeficiency virus (HIV-1) into megakaryocytes and that such infection may play a role in acquired immunodeficiency syndrome (AIDS)-related thrombocytopenia.

A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells.

Tre is a recombinant gene isolated from NIH3T3 cells transfected with human Ewing's sarcoma DNA. It is composed of three major genetic elements derived, 5' to 3', from human chromosomes 5, 18 and 17. We report here on transcripts from the 3' domain of tre. The transcripts were cloned from a cDNA library of cytoplasmic poly(A)+ RNA from tre-transfected NIH3T3 tumor cells. The complete cDNA sequence, 8201 nucleotides, possessed an unusually long non-coding region and a translatable region with two open reading frames. In one cDNA clone, the presence of two insertions suggested the possibility of alternative splicing. The sequence mapped to the centromere-proximal region of 17q. Transfection-tumorigenicity assays with the open reading frames subcloned into expression vectors were positive for the reading frame adjacent to the 5' non-coding region and negative for the second, downstream, reading frame and the possible alternatively spliced versions of both reading frames. Analysis of the 786 amino acid sequence deduced from the 5' reading frame predicted a highly hydrophilic protein with two charge clusters suggesting nucleic acid-binding properties. When used as probe, the cloned sequence detected RNA transcripts in a wide variety of human cancer cells regardless of their lineage of origin from different tissues, but not in human cells from normal tissue.

Receptor protein-tyrosine phosphatase gamma is a candidate tumor suppressor gene at human chromosome region 3p21.

PTPG, the gene for protein-tyrosine phosphatase gamma (PTP gamma), maps to a region of human chromosome 3, 3p21, that is frequently deleted in renal cell carcinoma and lung carcinoma. One of the functions of protein-tyrosine phosphatases is to reverse the effect of protein-tyrosine kinases, many of which are oncogenes, suggesting that some protein-tyrosine phosphatase genes may act as tumor suppressor genes. A hallmark of tumor suppressor genes is that they are deleted in tumors in which their inactivation contributes to the malignant phenotype. In this study, one PTP gamma allele was lost in 3 of 5 renal carcinoma cell lines and 5 of 10 lung carcinoma tumor samples tested. Importantly, one PTP gamma allele was lost in three lung tumors that had not lost flanking loci. PTP gamma mRNA was expressed in kidney cell lines and lung cell lines but not expressed in several hematopoietic cell lines tested. Thus, the PTP gamma gene has characteristics that suggest it as a candidate tumor suppressor gene at 3p21.

A new growth-regulated complementary DNA with the sequence of a putative trans-activating factor.

A new complementary DNA (cDNA) clone has been isolated by differential screening of a cDNA library. The cognate RNA of this clone, called SC1, is growth regulated in human, mouse, and hamster cell lines. Its kinetics of growth regulation (time of increase in mRNA levels, sensitivity to cycloheximide, behavior in G1-specific temperature-sensitive mutants) classify the SC1 gene as a late growth-regulated gene, like the histone genes and the genes coding for the proteins of the DNA synthesis apparatus. By run-on assay, there is a modest increase in transcriptional rates after serum stimulation, which is not sufficient to explain the sharp increase in mRNA levels. The SC1 gene localizes to human chromosome 6p21-22. In bacteria, the SC1 cDNA clone makes a protein of Mr 39,000, in agreement with the putative reading frame. The amino acid sequence derived from the cDNA sequence indicates a previously unknown gene with a domain strongly suggestive of a trans-activating domain. The SC1 gene can be considered as coding for a possible new trans-activating factor that could play an important role in the transcription of genes required for the later stages of cell cycle progression.