32 families informative for the segregation of Tuberous sclerosis (TSC) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4.7 at theta = 0) but other families were too small to give individually convincing lodscores. Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2.63) and with D16S291 on chromosome 16 (max lod 3.98) at values of theta of 0.2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the families linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC1 but in each case a single affected individual appeared to exclude the whole of the candidate region. Preliminary analysis of clinical features did not reveal any definite differences in incidence of mental handicap between individuals in different linkage groups or with different sex of the parent of origin. The frequencies of periungual fibromas and facial angiofibromas were also similar in both linkage groups. The difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be helpful in this respect.
Eight independent cell lines, derived from human testicular germ-cell tumors, were examined for the expression of various markers. These included major histocompatibility and embryonic antigens, chorionic gonadotropin, alpha fetoprotein, alkaline phosphatase, plasminogen activator, and infectivity by SV40. No line consisted primarily of choriocarcinoma or yolk sac cells, but several contained cells resembling murine embryonal carcinoma; some of these lines formed tumors with the distinctive features of embryonal carcinoma when injected into immunosuppressed animals. It is proposed that human embryonal carcinoma cells, unlike those of the mouse, correspond to a preblastocyst stage of development.
A human X chromosome‐derived gene sequence which recognises an abundant, 1.2‐kb mRNA in several cell types was previously isolated during a study to identify expressed sequences from an X chromosome recombinant library. Further characterisation of this clone, acronym OA1, has shown that it maps to the short arm of the X, at Xp21 to Xp22. A 777‐bp fragment of the clone which hybridizes to the 1.2‐kb mRNA has been sequenced, and the inferred amino acid sequence shows 80% homology with the published protein sequence for human muscle glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). The fragment shows even higher homology (87%) with pig muscle GAPDH. The OA1 clone selects an mRNA which translates in vitro into a polypeptide of 36 K, the subunit size of GAPDH. However, the X‐sequence is most probably a pseudogene whose structure is consistent with it having arisen by reverse transcription of a GAPDH or GAPDH‐related mRNA followed by insertion into the X chromosome. The GAPDH‐related portion of OA1 hybridizes to several DNA fragments in human and mouse DNA, and six fibroblast cDNA clones which cross‐hybridize to OA1 identify the same genomic fragments as OA1. This series of clones identifies a new, conserved GAPDH‐related multigene family.
A search for expression of heat-stable placental-type alkaline phosphatase (ALP) has been carried out in 19 unselected human tumor cell lines, known not to be HeLa. All cell lines showed measureable ALP activity and in 15 of the lines at least low levels of a heart-stable, presumptively placental-type ALP were detected. In five of these lines where the level of this heat-stable activity was sufficient, further, investigation, (immunologic, inhibition and electrophoretic studies) demonstrated that this ALP was placental-type in its characteristics and clearly different from liver/bone/kidney or intestinal ALPs. In 10 lines the heat-stable activity was too low to allow further characterization, In four lines no heat-stable activity in these various lines was liver-bone-kidney in type. This study suggests that the placental ALP locus may be expressed in at least at low levels in a much higher proportion of tumors and tumor cell lines than previously reported. The findings taken together with recent reports that low levels of placental-type ALP are present in some normal adult tissues (cervix, Goldstein et al., 1980; testis, Chang et al., 1980), indicate that so-called "ectopic" synthesis of placental ALP in tumor cells may not necessarily be due to derepression of a structural locus which is completely unexpressed in normal adult tissues. It may represent an enhancement of expression in malignancy or there may be clonal expansion of a particular cell type which normally expresses the alkaline phosphatase at a high level.
Forty loci (16 polymorphic and 24 non-polymorphic) together with 23 cosmids isolated from a chromosome 11-specific library were used to construct a detailed genetic map of 11p13-11q13. The map was constructed by using a panel of 13 somatic cell hybrids that sub-divided this region into 19 intervals, a meiotic mapping panel of 33 multiple endocrine neoplasia type 1 (MEN1) families (134 affected and 269 unaffected members) and a mitotic mapping panel that was used to identify loss of heterozygosity in 38 MEN1-associated tumours. The results defined the most likely order of the 16 loci as being: 11pter-D11S871-(D11S288, D11S149)-11cen-CNTF-PGA-ROM1-D11S480-PYGM- SEA-D11S913-D11S970-D11S97- D11S146-INT2-D11S971-D11S533-11qter. The meiotic mapping studies indicated that the most likely location of the MEN1 gene was in the interval flanked by PYGM and D11S97, and the results of mitotic mapping suggested a possible location of the MEN1 gene telomeric to SEA. Mapping studies of the gene encoding mu-calpain (CAPN1) located CAPN1 to 11q13 and in the vicinity of the MEN1 locus. However, mutational analysis studies did not detect any germ-line CAPN1 DNA sequence abnormalities in 47 unrelated MEN1 patients and the results therefore exclude CAPN1 as the MEN1 gene. The detailed genetic map that has been constructed of the 11p13-11q13 region should facilitate the construction of a physical map and the identification of candidate genes for disease loci mapped to this region.
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