R. S. Sparkes

Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis of glucose-6-phosphate dehydrogenase

The use of electrophoretic types of the X-linked enzyme G-6-PD to study the cellular origin of leiomyomas is reported. Previous studies by Linder and Gartler, suggesting a unicellular origin for leiomyomas, are confirmed and extended. When only a few tumors were present they tended to be of the same G-6-PD type. However, when many tumors were present, tumors of both type A and type B were found in the same uterus. The principles of using a cell marker, such as G-6-PD, to determine the cellular origin of tumors are reviewed. The results of using this technique with other benign as well as malignant tumors are summarized. Limitations in the interpretation of results with this system are noted.

Assignment of human 3-hydroxy-3-methylglutaryl coenzyme A reductase gene to q13 → q23 region of chromosome 5

We have used hamster cDNA probes for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (HMGCR) to determine the chromosomal location of the human gene for HMG CoA reductase. Southern blot analysis of genomic DNA from 16 independent mouse-human somatic cell hybrids showed that the human gene for HMG CoA reductase resides on chromosome 5. Analysis of Chinese hamster-human somatic cell hybrids selectively retaining human 5 or a portion of it showed that the gene locus for HMG CoA reductase can be assigned to the q13 → q23 region of chromosome 5.

Juvenile myoclonic epilepsy in chromosome 6p12‐p11: Locus heterogeneity and recombinations

We recently analyzed under homogeneity a large pedigree from Belize with classic juvenile myoclonic epilepsy (JME). After a genome wide search with 146 microsatellites, we obtained significant linkage between chromosome 6p markers, D6S257 and D6S272, and both convulsive and EEG traits of JME. Recombinations in two affected members defined a 40 cM JME region flanked by D6S313 and D6S258. In the present communication, we explored if the same chromosome 6p11 microsatellites also have a role in JME mixed with pyknoleptic absences. We allowed for heterogeneity during linkage analyses. We tested for heterogeneity by the admixture test and looked for more recombinations. D6S272, D6S466, D6S294, and D6S257 were significantly linked (Zmax > 3.5) to the clinical and EEG traits of 22 families, assuming autosomal dominant inheritance with 70% penetrance. Pairwise Zmax were 4.230 for D6S294 (theta m = f at 0.133) and 4.442 for D6S466 (theta m = f at 0.111). Admixture test (H2 vs. H1) was significant (P = 0.0234 for D6S294 and 0.0128 for D6S272) supporting the hypotheses of linkage with heterogeneity. Estimated proportion of linked families, alpha, was 0.50 (95% confidence interval 0.05-0.99) for D6S294 and D6S272. Multipoint analyses and recombinations in three new families narrowed the JME locus to a 7 cM interval flanked by D6S272 and D6S257.

CLOSE GENETIC LINKAGE BETWEEN DIABETES MELLITUS AND KIDD BLOOD GROUP

27 polymorphic genetic markers were analysed for possible linkage with insulin-dependent diabetes mellitus (IDDM). The data set contained 71 families with at least one affected member each. Under three different genetic models for IDDM, evidence was found for linkage between the disease and two distinct sets of marker loci: three markers on chromosome 6 (HLA, properdin factor B, and glyoxalase-1), and the Kidd blood group locus. The families apparently do not fall into two groups, one exhibiting linkage to the HLA complex and the other to the Kidd locus. Thus, two distinct disease-susceptibility loci may be involved in the inheritance of IDDM.

Evidence for a null allele at the esterase D (EC 3.1.1.1) locus.

SummaryElectrophoretic and quantitative assays of esterase D in a Caucasian family demonstrate the inheritance of a null allele, which was observed in the heterozygous state in six individuals.

BONE-MARROW TRANSPLANTATION FOR METACHROMATIC LEUCODYSTROPHY

An 11-month-old boy with late infantile metachromatic leucodystrophy was given a bone-marrow transplant (BMT) from an HLA-identical sister; 6 months later his cerebrospinal fluid leucocytes were exclusively of donor origin. Coupled with the patients continued developmental progress, as assessed 33 months after the procedure, the findings suggest that BMT may be an effective treatment for some congenital metabolic disorders which affect the central nervous system.

DO ONCOGENES DETERMINE CLINICAL FEATURES IN CHRONIC MYELOID LEUKAEMIA

Oncogene abnormalities are thought to have a central role in some human malignant disorders, particularly Burkitt leukaemia/lymphoma and chronic myeloid leukaemia (CML). However, the extent to which specific oncogene changes determine the clinical features of these disorders is unknown. This question was studied in two groups of patients with CML negative for the Philadelphia (Ph) chromosome; one group showed clinical features typical of Ph-positive CML and the other group lacked such features. Molecular findings were compared with those of Ph-positive CML. In all ten patients there was evidence for rearrangement of the bcr (breakpoint cluster region) gene. In the four cases studied the c-abl proto-oncogene was translocated to chromosome 22 and in five cases there was transcription of a chimeric bcr-abl mRNA. Thus, the molecular abnormality is the same in both groups of Ph-negative CML and identical to that in Ph-positive CML. Factors other than the bcr/c-abl rearrangement must underlie the clinical heterogeneity of CML.

Tissue specificity of chromosomal rearrangements in ataxia-telangiectasia

SummaryCytogenetic studies of lymphocytes and fibroblasts from individuals with ataxia-telangiectasia (AT) demonstrate spontaneous chromosomal breakage. In the AT lymphocytes, this damage results in a high frequency of balanced rearrangements involving chromosome bands 7p14, 7q35, 14q12, and 14q32. The T-cell receptor α, β, and γ chain gene complexes and the immunoglobulin heavy chain gene complex, all of which may be functional in lymphocytes, have been localized to these bands. To assess the relationship between genes at these breakpoints and the entirety of the AT phenotype, we undertook a detailed cytogenetic analysis of fibroblasts and lymphocytes from seven AT homozygotes. Our findings indicate that the rearrangements present in the lymphocytes are not commonly observed in the fibroblasts, despite the increased instability of chromosomes from these cells relative to lymphocytes. Furthermore, the changes in the fibroblasts are neither consistent within nor between patients, suggesting that chromosome rearrangement occurs more randomly in this tissue. Therefore, differential site-specific damage in separate tissues may generate the distinct features of the disease in those tissues and may account for the pleiotrophic effects of the AT gene.

Regional localization of the human genes for S-adenosylhomocysteine hydrolase (cen→q131) and adenosine deaminase (q131→qter) on chromosome 20

SummaryThe gene loci for S-adenosylhomocysteine hydrolase (AHCY) and adenosine deaminase (ADA), two enzymes with related metabolic functions, have both been assigned to human chromosome 20. We have used rodent-human somatic hybrids containing translocations involving human chromosome 20 to more precisely determine the relative locations of the AHCY and ADA loci. Our results assign the AHCY locus to the long arm of chromosome 20, in the region cen→q131, and ADA to the region q131→qter.

Regional mapping of ADA and ITP on human chromosome 20: cytogenetic and somatic cell studies in an X/20 translocation

An apparently balanced de novo translocation between chromosomes X and 20, 46,X,t(X;20)(Xp20q;Xq20p), was identified in a severely retarded 13-year-old female with macrocephaly, bilateral overfolded pinnae, elbow contractures, clinodactyly, and seizures. BudR-pulse studies show the normal X chromosome to be late replicating in both lymphocytes (50 cells) and skin fibroblasts (25 cells). An HPRT deficient Chinese hamster line was fused with lymphocytes from the patient, and hybrid lines were derived in HAT medium. Cytogenetic and biochemical analyses of these hybrid lines show that the locus for adenosine deaminase is in the cen leads to qter region and that the locus for inosine triphosphatase is in the pter leads to cen region of human chromosome 20.