Mapping studies of the serum cholinesterase-2 locus (CHE2).

Serum cholinesterase (butyrylcholinesterase, EC 3.1.1.8, BChE) is controlled by two genetic loci, CHE1 and CHE2. The CHE1 locus has been mapped to 3q, but the map location of CHE2 is uncertain. In an effort to clarify the location of CHE2, we combined all the published linkage analysis data for CHE2 (as summarized in the Keats Linkage Database) with the data from the UCLA Linkage Database. Exclusions with substantial portions of the genome could be made (notably with portions of chromosomes 1, 2, 3, 4, 6, 7, 8, 9, 14, 16, 18, 19, 20, 22, and LG1). Although not quite statistically significant (zeta = 2.51), loose linkage (theta = 0.32) of CHE2 with the haptoglobin locus on 16q22 was the most likely conclusion from the family data. In addition, calculating the lod score between CHE2 and the available linkage map of chromosome 16 (markers HBA, PGP, FRA16A, and HP) resulted in an overall lod score of 3.2. This result is particularly intriguing given the hybridization of a BChE cDNA (designated CHEL3) to the same region. Resolution of the issue will require more detailed linkage studies of CHE2 on chromosome 16 and a better understanding of the relationship between the CHE1 and CHE2 loci with respect to production of serum cholinesterases.

Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI.

We report the regional mapping of human chromosome 19 genes for three apolipoproteins and a lipoprotein receptor as well as genes for three other markers. The regional mapping was made possible by the use of a reciprocal whole-arm translocation between the long arm of chromosome 19 and the short arm of chromosome 1. Examination of three separate somatic cell hybrids containing the long arm but not the short arm of chromosome 19 indicated that the genes for apolipoproteins CI, CII, and E (APOC1, APOC2, and APOE, respectively) and glucose-6-phosphate isomerase (GPI) reside on the long arm, whereas genes for the low density lipoprotein receptor (LDLR), complement component 3 (C3), and peptidase D (PEPD) reside on the short arm. When taken together with previous studies, our results suggest the following physical gene map: pter-LDLR-C3-p13.2-PEPD-centromere-(APOE, APOC1, APOC2, GPI)-qter. In addition, we have isolated a single lambda phage carrying both APOC1 and part of APOE. These genes are tandemly oriented and are separated by about 6 kilobases of genomic DNA. Since previous family studies indicate tight linkage of APOE and APOC2, the apolipoprotein genes APOC1, APOC2, and APOE form a tight complex on the long arm of chromosome 19, suggesting the possibility of coordinate regulation.

Linkage analyses of multiple endocrine neoplasia, type 2 (MEN-2) with 23 classical genetic polymorphisms.

Linkage analyses were performed in a single large family with multiple endocrine neoplasia, type 2 (MEN-2) between 23 classical genetic polymorphisms and MEN-2. We exclude close linkage of the locus for MEN-2 with ABO, ACP1, BF, ESD, Fy, GALT, GLO1, Jk, MNSs, P, PGM1, Rh and TF, as well as absolute linkage with GPT. These results raise to about 6% the proportion of the genome that has been excluded in this one family. Somewhat positive lod scores were obtained for GC (0.92 at theta = 0), GPT (0.73 at theta = 0.1) and HP (1.49 at theta = 0.05); although not statistically significant, these findings suggest regions of the genome that warrant additional study.

Evidence from somatic cells for crossing-over in humans.

Chromosomal and gene marker studies of somatic cells in a family with multiple chromosome translocations show apparent instability of the translocations in transmission from generation to generation. This instability is attributed to meiotic crossing-over between the involved chromosomes. Technical advances in chromosome analysis combined with human gene map information in the study of this unusual family demonstrate for the first time that crossing-over involves exchange of chromatin between nonsister chromatids of homologous chromosomes.

Glutamate pyruvate transaminase null allele (GPT0) in the Navajo.

During genetic linkage studies of retinitis pigmentosa in a Navajo Amerindian family, an apparent null allele of erythrocyte GPT (GPT0) was observed in a man and 2 of his daughters. This is the fourth description of a (GPT0) allele, the first outside of Europe and the first in the Navajo.

Genetic linkage analysis of the carpal tunnel syndrome.

Two generations of a family with autosomal dominant carpal tunnel syndrome were studied for genetic linkage to 20 informative polymorphic blood markers. No linkage was demonstrated between the syndrome and the markers tested; exclusion of close linkage (lod score less than -2.0) was found for MNSs, ACP, GALT, GPT, GLO, Hp, Gc, and Pi.

Aniridia: enzyme studies in an 11p--chromosomal deletion.

A patient with aniridia and an interstitial deletion of the bands p13-p14 of the short arm of chromosome 11 was studied to determine the relative locations of the gene(s) encoding for the aniridia-Wilms' tumor association with other genes on the same chromosome. Quantitative analysis was performed on the red blood cell enzymes lactic acid dehydrogenase-A (LDH-A) and catalase, the genes for which are located on the short arm of chromosome 11. The activity of LDH-A was normal; the activity of catalase was reduced to approximately half normal. This evidence supports loci for the genes encoding for both catalase and the aniridia-Wilms' tumor association within the bands p13-p14 of the short arm of chromosome 11; the normal activity of LDH-A supports a locus outside this region.

Transferase-deficiency galactosemia: immunochemical studies of the Duarte and Los Angeles variants.

Rabbit antibodies to purified human placental galactose-1-phosphate uridyltransferase (EC 2.7.7.12) were used to establish immunologic cross-reactivity patterns for the enzyme in hemolysates, prepared from red cells of a normal individual, a homozygous Duarte variant, and a heterozygous Los Angeles variant. The antibody immunoprecipitated all three forms of the enzyme. The amount of antibody absorbed by each hemolysate was related to the different levels of activity, and examination of hemolysate/antibody reaction mixtures by starch gel electrophoresis revealed that the antibody quantitatively precipitated all of the isoenzyme forms that characterize these three genetic variants.

Evidence of autonomous red cell expression of Xga antigen in human bone marrow transplantation.

Human bone marrow transplant chimeras afford the opportunity to determine whether a red blood cell antigen is autonomously controlled. Evaluation of an Xg(a-) recipient and an Xg(a+) recipient, each transplanted with bone marrow of donors of opposite Xga types, shows that the Xga antigen is of the donor type following transplantation. This indicates that the Xga antigen is controlled by the red blood cell, and confirms earlier studies in natural chimeras.

Separation of retinoblastoma and esterase D loci in a patient with sporadic retinoblastoma and del(13)(q14.1q22.3).

A chromosome 13 deletion in a patient with sporadic retinoblastoma appears to have separated the loci for retinoblastoma and esterase D. This study indicates that: (1) the retinoblastoma locus is distinct from the esterase D locus; and (2) the linear order of these genes is centromere-esterase D-retinoblastoma.

Genetic linkage studies of transferrin, pseudocholinesterase, and chromosome 1 loci.

Genetic linkage analysis of a pedigree with four different alleles for pseudocholinesterase (CHE1) gives a positive lod score of 0.37 at theta = 0.16 for linkage with transferrin (TF), a finding which supports previous reports of linkage between CHE1 and TF. Evaluation of linkage relations of CHE1 and TF using unreported families from our data bank fails to establish linkage with chromosome 1 loci (6-PGD, Rh, PGM1, AMY2 and FY). These results are consistent with recent studies which suggest that TF is on human chromosome 3.

Association studies between Type 1 (insulin-dependent) diabetes and 27 genetic markers: lack of association between Type 1 diabetes and Kidd blood group.

One hundred and three unrelated patients with Type 1 (insulin-dependent) diabetes were typed for HLA, properdin factor B (BF), glyoxalase 1 (GLO), Kidd blood group, and 24 other genetic markers. Observed distributions of marker phenotypes among these patients were compared with those expected according to population frequencies, in an attempt to detect associations between Type 1 diabetes and the markers. Strong associations between Type 1 diabetes and both HLA and properdin factor B were confirmed, as was a lack of association between Type 1 diabetes and glyoxalase (GLO). There was an apparent deviation from Hardy-Weinberg equilibrium at the GLO locus, and statistically significant distortions in the distributions of pancreatic amylase (AMY2), galactose-1-phosphate uridyl transferase (GALT), and group-specific component (GC) among Type 1 diabetes patients, but these results are not significant when corrected for performance of multiple tests. An increase in the Lewis-negative phenotype reported elsewhere was observed here but was not statistically significant. A distortion in the distribution of Kidd types reported elsewhere was not confirmed.

Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene.

Although a constitutional chromosomal deletion including 13q14 has been found to date in all retinoblastoma patients whose esterase D activity is 50 percent of normal, one female patient has been found who has 50 percent esterase D activity in all normal cells examined but no deletion of 13q14 at the 550-band level. Therefore, she has the smallest constitutional chromosomal deletion within 13q14 that is associated with susceptibility to retinoblastoma. Two stem lines were identified in a retinoblastoma from this patient, and each one had a missing 13 chromosome. No detectable esterase D activity was found in the tumor, indicating that the normal nondeleted 13 chromosome was lost in both stem lines. Thus the data from this patient not only show that there is a total loss of genetic information at the location of the retinoblastoma gene within the tumor, but also imply that recessive genes may play an important role in the development of certain human tumors including retinoblastoma.

Gene for hereditary retinoblastoma assigned to human chromosome 13 by linkage to esterase D.

Evaluation of three families with hereditary retinoblastoma demonstrates close linkage of the gene for this tumor with the genetic locus for esterase D. These results assign the gene for the hereditary form of retinoblastoma to band q14 on chromosome 13, the same region which is affected in the chromosome deletion form of this eye tumor, and therefore suggest a common underlying mechanism in the pathogenesis of these two forms of retinoblastoma.

Trisomy 20p due to a paternal reciprocal translocation.

A mentally retarded boy with multiple malformations was found to have trisomy for the distal two-thirds of the short arm of chromosome 20 (trisomy 20p), resulting from a paternal translocation (5;20)(p15;p11). The patient had a cleft palate, a feature not present in other trisomy 20p patients. A review of the reported trisomy 20p patients indicates that their varied features do no constitute a readily recognizable clinical syndrome.

Glutamate pyruvate transaminase null allele in seven new families.

Based upon aberrant segregation of glutamate pyruvate-transaminase (GPT) and reduced enzyme activity on electrophoresis, seven new families with a GPT null allele were identified during genetic linkage analysis for a number of different traits.

Glyoxalase I "null" allele in a new family: identification by abnormal segregation pattern and quantitative assay.

A GLO-I "null" allele in a family was indicated by an abnormal segregation pattern and by half normal red cell enzyme activity in carriers. This is the third reported instance of this uncommon allele, and the first with confirmation by quantitation of enzyme activity.

The human phosphoserine phosphatase gene (PSP) is mapped to chromosome 7 by somatic cell genetic analysis.

Human phosphoserine phosphatase (E.C. 3.1.3.3) (PSP), a phosphohydrolase, participates in the biosynthesis of serine from carbohydrates (Moro-Furlani et al., 1980). Starch gel electrophoresis has identified isoenzymes and rare allelic variants. More common electrophoretic variation is thought to be due to secondary nongenetic modification. Using starch gel electrophoresis of interspecific somatic cell hybrids, we have been able to assign the gene for this enzyme to human chromosome 7.

Linkage analysis of five pedigrees affected with typical autosomal dominant retinitis pigmentosa.

Five pedigrees (including an expanded version of a previously reported pedigree) exhibited typical autosomal dominant retinitis pigmentosa were analysed for linkage of RP to 29 genetic markers. No significant lod scores resulted. The largest lod score is +1.51 and suggests linkage between RP and Rh blood group at an estimated recombination fraction of 20% in males and 40% in females. Further studies are needed to confirm or refute this suggested linkage.