Seventeen independently derived primary mouse-human hybrid clones were scored for the expression of human phosphoglycolate phosphatase (PGP) by electrophoresis and for the presence of human chromosomes with the aid of Q banding. The correlation of biochemical and cytogenetic analyses shows that the segregation of human PGP in these hybrids is concordant only with human chromosome 16, thus enabling the assignment of the genetic locus for PGP to human chromosome 16.

Association studies of the minor TaqI A allele of the D(2) dopamine receptor (DRD2) gene with alcoholism have produced conflicting findings. Failure to assess alcoholics for severity of their disorder and to screen controls for substance use have been proposed as causes for the discrepant results. In the present study, five diallelic sites spanning the DRD2 gene were determined in combined Caucasian (non-Hispanic) studies of more severe alcoholics (n = 92) and controls screened for substance use (n = 85). The frequency of the minor alleles at the 3'-untranslated site (TaqI A) and two intronic sites (TaqI B and intron 6) of the DRD2 gene were each strongly associated with alcoholism. Moreover, the alcoholics compared with the controls at these three sites had a significantly higher frequency of the minor/major allele heterozygote haplotype combination (A1/A2 B1/B2 T/G) than the major allele homozygote haplotype combination (A2/A2 B2/B2 G/G). However, exon 7 and promoter alleles were not associated with alcoholism. In neither the alcoholics nor in the controls were there departures from Hardy-Weinberg equilibrium at any of the five sites examined. The most significant diallelic composite genotypic disequilibria were found when comparisons were made between TaqI A and TaqI B, TaqI A and intron 6, and TaqI B and intron 6 sites. Weaker but still significant disequilibria were observed when TaqI A and exon 7, TaqI B and exon 7, intron 6 and exon 7, and promoter and exon 7 sites were compared. However, no significant disequilibria were noted when TaqI A and promoter, TaqI B and promoter, and intron 6 and promoter sites were compared. In sum, the study found significant evidence for association of the minor alleles in the untranslated sites of the DRD2 gene and their haplotypes with the more severe alcoholic phenotype.

PURPOSE:To map the gene for autosomal dominant cataracts (ADC) in an American white family of European descent.METHODS:Ophthalmic examinations and linkage analyses using a variety of polymorphisms were performed; two-point lod scores calculated.RESULTS:Affected individuals (14 studied) exhibited variable expressivity of embryonal nuclear opacities based on morphology, location within the lens, and density. This ADC locus to 12q13 was mapped on the basis of statistically significantly positive lod scores and no recombinations (theta(m) = theta(f) = 0) with markers D12S368, D12S270, D12S96, D12S359, D12S1586, D12S312, D12S1632, D12S90, and D12S83; assuming full penetrance, a maximum lod score of 4.73 was calculated between the disease locus and D12S90.CONCLUSIONS:The disease in this family represents the first ADC locus on chromosome 12; major intrinsic protein of lens fiber (MIP) is a candidate gene.

We conducted linkage analysis of 64 multiple-case families with early-onset bilateral breast cancer using DNA markers on chromosome band 1p36. Evidence against tight linkage was obtained using a dominant model for transmission (summary LOD scores at recombination fraction theta = 0.000001 were -4.71 for D1S160 and -2.70 for D1S170). Similar results were obtained after excluding 20 families that were potentially attributable to BRCA1 or BRCA2. We also investigated loss of heterozygosity for a panel of markers on chromosome arm 1p using breast tumors from affected family members. The most common regions of allele loss were 1p36 (32% for D1S160, 35% for D1S243) and 1p32 (51% for MYCL). The frequency and location of 1p allele loss did not differ substantially from previous studies of sporadic breast cancer. We conclude that 1p36 probably does not contain a locus of susceptibility for a large proportion of breast cancer families, but a variety of loci on 1p may contribute to progression of familial and sporadic disease. Genes Chromosomes Cancer 25:354-361, 1999.

Among the 40 to 100 million persons with epilepsy worldwide and the 2 to 2.5 million persons with epilepsies in the United States, approximately 50% have generalized epilepsies. Among all epilepsies, the most common are juvenile myoclonus epilepsy (JME) with 10% to 30% of cases, childhood absence epilepsy (CAE) with 5% to 15% of cases, and pure grand mal on awakening with 22% to 37% of cases. In the last decade, six different chromosomal loci for common generalized epilepsies have been identified. These include two separate loci for JME in chromosomes 6p and 15q. The epilepsy locus in chromosome 6p expresses the phenotypes of classic JME, pure grand mal on awakening, and possibly JME mixed with absences. Two separate loci also are present for pyknoleptic CAE, namely, CAE that evolves to JME in chromosome 1p and CAE with grand mal in chromosome 8q24. Pandolfo et al. from the Italian League Against Epilepsy have reported two other putative susceptibility loci for idiopathic generalized epilepsies, namely, grand mal and generalized spike waves 35l in chromosome 3p and generalized epilepsies with febrile convulsions, grand mal, JME, absences, and electroencephalographic spike waves in 8q24. This chapter reports on the debate concerning whether there may be two separate epilepsy loci in chromosome 6p, one in the HLA region and one below HLA. The chapter then discusses the progress made in our laboratories as a result of the Genetic Epilepsy Studies (GENES) International Consortium. We discuss (a) the 2 to 6 cM critical region for classic JME located some 20 cM below HLA in chromosome 6p, (b) the 7-cM area for pyknoleptic CAE that evolves to JME in chromosome 1p, and (c) the 3.2 cM area for pyknoleptic CAE with grand mal and irregular 3 to 4 Hz spike waves in chromosome 8q24. We discusses efforts underway to refine the genetic map of JME in chromosome 6p11 and the advances in physical mapping and positioning of candidate genes, such as the gamma-aminobutyric acid receptor gene, the potassium channel gene of the long-QT family (KvLQT), named KCNQ3, and the human homologue of the mouse jerky gene for CAE in chromosome 8q24 and JME in chromosome 6p11.

The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D2 dopamine receptor (DRD2) and D4 dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1, B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered.

To the Editor: Lafora disease (LD) is an autosomal recessive and rare but fatal epilepsy syndrome characterized by stimuli-sensitive myoclonus, absence and grand mal seizures, progressive intellectual and neurological deterioration, and periodic acid Schiff (PAS) stain–positive intracellular inclusion bodies. Eighty-four years after Gonzalo Lafora (Lafora, 1911aLafora GR The presence of amyloid bodies in the protoplasm of the ganglion cells: a contribution to the study of the amyloid substance in the nervous system.Bull Gov Hosp Insane. 1911a; 3: 83-92Google Scholar, Lafora, 1911bLafora GR Über das Vorkommen amyloider Körperchen im Innern der Ganglienzellen: zugleich Ein zum Studium der amyloiden Substanz im Nervensystem.Virchows Arch A Pathol Anat Histopathol. 1911b; 205: 295-303Crossref Scopus (91) Google Scholar) first described such PAS-positive “intracellular amyloid bodies” in the CNS of a young adult who died from a progressive myoclonus epilepsy, we encountered extended areas of homozygosities in chromosome 6q23-25 in nine LD patients who were products of consanguineous marriages (families LD1, LD4, LD5, and LD9). We also detected significant linkage to chromosome 6q23-25 microsatellites in one large inbred family, LD9, and thus localized the LD gene to a 17-cM interval on chromosome 6q23-25, between D6S292 and D6S420 (Serratosa et al., 1995Serratosa JM Delgado-Escueta AV Posada I Shih S Drury I Berciano J Zabala JA et al.The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q.Hum Mol Genet. 1995; 4: 1657-1663Crossref PubMed Scopus (100) Google Scholar). To reduce the size of the 17-cM candidate region, we have studied an expanded series of 39 biopsy-proved LD patients who belong to 26 unrelated families (12 inbred) from Spain, Canada, France, the United States, Palestine, Iran, Ecuador, and Saudi Arabia. We provide further proof for significant linkage of LD to chromosome 6q24 in a second and new large inbred family (LD33). Homozygosities and recombinations in six new informative families reduce the size of the previously reported 17-cM LD interval to 2.7 cM flanked centromerically by D6S1003 and telomerically by D6S311. The clinical diagnosis of LD was initially established by the referring physician and was corroborated by the senior epileptologist in this study. PAS-positive inclusion bodies were demonstrated in skin and/or muscle and in liver and/or brain biopsies of all affected family members, including affected individuals carrying recombinant chromosomes. High-molecular-weight DNA was extracted either from 10 ml of venous blood from living family members, by use of phenol/chloroform followed by isopropanol precipitation (Sambrook et al., 1989Sambrook J Fritsch EF Maniatis T Molecular cloning: a laboratory manual. 2d ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1989Google Scholar), or from 200 μl of peripheral blood by use of the QUIAamp blood kit (Qiagen). DNA from deceased family members (LD9-10, LD9-12, LD9-16, LD18-3, and LD19-3) was extracted from paraffin-embedded archived autopsy specimens of liver, brain, and muscle (Jackson et al., 1990Jackson D Lewis F Taylor G Boylston A Quirke P Tissue extraction of DNA and RNA analyzed by the polymerase chain.J Clin Pathol. 1990; 43: 499-504Crossref PubMed Scopus (227) Google Scholar; Greer et al., 1991Greer C Petersen S Kiviat N Manos M PCR amplification from paraffin-embedded tissues.Anat Pathol. 1991; 95: 117-124Google Scholar). All primers for amplification were obtained from Research Genetics. The method of Weber and May, 1989Weber JL May PE Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction.Am J Hum Genet. 1989; 44: 388-396PubMed Google Scholar was used to type highly polymorphic short tandem repeats or microsatellites (heterozygosity >.7) in 50 parents and in 39 affected and 56 unaffected individuals. Parametric or model-dependent two-point linkage analyses using LINKAGE 5.1 (Ott, 1974Ott J Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies.Am J Hum Genet. 1974; 26: 588-597PubMed Google Scholar) were performed in eight multiplex families (LD3, LD4, LD6, LD9, LD12, LD27, LD28, and LD33) and in five simplex consanguineous families (LD1, LD5, LD7, LD22, and LD25). We estimated the frequency of the disease allele to be .001, and penetrance was set at 100%, assuming an autosomal recessive model. The gene mutation rate was set at 0. We calculated LOD scores at recombination fractions (θm=f). We performed multipoint linkage analyses in family LD33, using a new software package, GENEHUNTER (Kruglyak et al., 1996Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar). We first looked for recombinations and homozygosities (Lander and Botstein, 1987Lander ES Botstein D Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.Science. 1987; 236: 1567-1570Crossref PubMed Scopus (660) Google Scholar) in families LD9 and LD33, because they provided independent proof for linkage to chromosome 6q24. We had previously published significant LOD scores obtained during two-point analyses in family LD9 (Serratosa et al., 1995Serratosa JM Delgado-Escueta AV Posada I Shih S Drury I Berciano J Zabala JA et al.The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q.Hum Mol Genet. 1995; 4: 1657-1663Crossref PubMed Scopus (100) Google Scholar). We used the new generation of microsatellites in family LD9 but did not reduce the size of the 17-cM LD region, flanked centromerically by D6S292 and telomerically by D6S420, that we had reported in 1995. In family LD33, the LOD score for D6S1703 was 3.24 (θm=f = 0) during two-point analyses (Ott, 1974Ott J Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies.Am J Hum Genet. 1974; 26: 588-597PubMed Google Scholar), exceeding the threshold for significance. We also computed 10-point LOD scores (Kruglyak et al., 1996Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar) in family LD33, against a fixed genetic map with nine markers (D6S308, D6S409, D6S1003, D6S1010, D6S1703, D6S1042, D6S311, D6S978, and D6S420) in an 11-cM region surrounding the LD gene. During multipoint analysis, we obtained maximum location scores of 4.03 for markers D6S1010, D6S1703, and D6S1042, which are situated between D6S1003 and D6S311. Recombinations and homozygosities in LD33 were consistent with results of two-point and multipoint analyses and reduced the size of the LD-gene region to the interval flanked by D6S1003 and D6S1687 (fig. 1). Homozygosities in all three living affected members (see haplotypes of LD33-3, LD33-5, and LD33-6; fig. 1) involved 20–27 microsatellites, covering 13–17 cM. These homozygosities indicated that the three affected individuals inherited two copies of the same mutation from a common ancestor—in this case, a grandmother—six generations earlier. A recombination between D6S1553 and D6S1687 in LD33-6 determined that the telomeric border of the LD region is D6S1687. In addition, a recombination centromeric to the LD locus, between D6S1003 and D6S1010, in individual LD33-3 further identified the centromeric border of the LD region, as being D6S1003. These two recombinations (see fig. 1, arrows) effectively reduced the critical LD interval, to ∼7 cM flanked centromerically by D6S1003 and telomerically by D6S1687. Our second level of analyses looked at families whose extended regions of homozygosities strongly supported the presence of an LD locus in chromosome 6q24, even though the small sizes of their families precluded LOD scores from reaching significance. Homozygosities in families LD20 and LD22 show the centromeric flanking marker to be D6S308 and D6S403, respectively (see fig. 1). Data on LD22 are not shown. These observations verify the general vicinity of the centromeric border of the LD region, since D6S403 and D6S308 are <2 cM from D6S1003. They lend support to the observation, in family LD33, of D6S1003 as the centromeric flanking marker. Three proofs support D6S311 as the telomeric border of the LD gene. First, homozygosities in family LD15 identify the telomeric border as D6S1553, and results for family LD16 cut the LD region further and identify D6S311 as the telomeric flanking marker (see fig. 1). Second, another family, LD17, has loss of homozygosity at the telomeric end in D6S311, but we were unable to genotype for the new generation of markers in the interval spanned by D6S1003 and D6S311, because of the minute amounts of DNA obtained from archived paraffin-embedded tissues. Although the genotypes for these new microsatellites are missing, the existing data support D6S311 as the telomeric flanking marker in family LD17 (data not shown). Third, a recombination between D6S311 and D6S978 in family LD15 (see fig. 1, arrows) provides further proof that D6S311 is the telomeric border of the disease gene. In summary, we reduced the size of the LD interval to 2.7 cM flanked by D6S1003 and D6S311, by (a) correlations between recombinations and homozygosities in a new large family (LD33), which, by itself, independently proved linkage to chromosome 6q24 microsatellites, (b) extended area of homozygosities in affected members of smaller families (LD15, LD16, LD17, LD20, and LD22), and (c) a recombination in family LD15. What kind of gene might be responsible for Lafora progressive myoclonus epilepsy? If the gene responsible for LD is involved in the degradation pathways of glycoprotein metabolism (Lafora, 1955Lafora GR Myoclonus: physiological and pathological considerations.in: In: Proceedings of the 2d International Congress of Neuropathology. Part 1. Excerpta Medica, Amsterdam1955: 9-21Google Scholar; Schwarz and Yanoff, 1965aSchwarz GA Yanoff M Lafora bodies, corpora amilacea, and Lewy bodies: a morphological and histochemical study.Arch Neurobiol (Madrid). 1965a; 28: 800-818Google Scholar, Schwarz and Yanoff, 1965Schwarz GA Yanoff M Lafora's disease: distinct clinico-pathologic form of Unverricht's syndrome.Arch Neurol. 1965; 12: 172-188Crossref PubMed Scopus (83) Google Scholar; Yokoi et al., 1968Yokoi S Austin J Witmer F Sakai M Studies in myoclonus epilepsy (Lafora body form). I. Isolation and preliminary characterization of Lafora bodies in two cases.Arch Neurol. 1968; 19: 15-33Crossref PubMed Scopus (110) Google Scholar; Sakai et al., 1970Sakai M Austin J Witmer F Trueb L Studies in myoclonus epilepsy (Lafora body form). II. Polyglucosans in the systemic deposits of myoclonus epilepsy and in corpora amylacea.Neurology. 1970; 20: 160-176Crossref PubMed Google Scholar; Gambetti et al., 1971Gambetti P Di Mauro S Hirt L Blume RP Myoclonic epilepsy with Lafora bodies.Arch Neurol. 1971; 25: 483-493Crossref PubMed Scopus (63) Google Scholar; Schwarz, 1977Schwarz GA Lafora's disease: a disorder of carbohydrate metabolism.in: Goldensohn ES Appel SH Scientific approaches to clinical neurology. Lea & Febiger, Philadelphia1977: 148-159Google Scholar; Federico et al., 1980Federico A D'Amore I Palladini G Medolago-Albani L Guazzi GC Tomaccini D Lafora's disease: clinical, histological ultrastructural and biochemical study.Acta Neurol. 1980; 2: 466-475PubMed Google Scholar), the alpha fucosidase-2 gene (FUCA2), located on chromosome 6q24, would be a candidate gene. FUCA2 is tightly linked to the protein marker, plasminogen (Eiberg et al., 1984Eiberg H Mohr J Nielsen LS Linkage of plasma alpha-L-fucosidase (FUCA2) and the plasminogen (PLG) system.Clin Genet. 1984; 26: 23-29Crossref PubMed Scopus (31) Google Scholar), which, in turn, is genetically linked to chromosome 6q (Murray et al., 1987Murray JC Buetow KH Donovan M Hornung S Motulsky AG Disteche C Dyer K et al.Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26-6q27.Am J Hum Genet. 1987; 40: 338-350PubMed Google Scholar). A second candidate gene that maps to chromosome 6q22.3-q24 is that for L-isoaspartyl/D-aspartyl protein methyltransferase, or protein carboxyl methyltransferase 1 (PCMT1) (MacLaren et al., 1992MacLaren DC O'Connor CM Xia YR Mehrabian M Klisak I Sparkes RS Clarke S et al.The L-isoaspartyl/D-aspartyl protein methyltransferase gene (PCMT1) maps to human chromosome 6q22.3-6q24 and the syntenic region of mouse chromosome 10.Genomics. 1992; 14: 852-856Crossref PubMed Scopus (18) Google Scholar), which is involved in repair of proteins (Ota et al., 1988Ota IM Gilbert JM Clarke S Two major isozymes of the protein D-aspartyl/L-isoaspartyl methyltransferase from human erythrocytes.Biochem Biophys Res Commun. 1988; 151: 1136-1143Crossref PubMed Scopus (21) Google Scholar). PCMT1 catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the free carboxyl groups of D-aspartyl and L-isoaspartyl residues, which represent sites of covalent damage to aging proteins. LD may represent a disorder of protein repair, and the “intracellular amyloid inclusion bodies” could be evidence of impaired protein repair (Tsai and Clarke, 1994Tsai W Clarke S Amino acid polymorphisms of the human l-isoaspartyl/d-aspartyl methyltransferase involved in protein repair.Biochem Biophys Res Commun. 1994; 203: 491-497Crossref PubMed Scopus (15) Google Scholar). We thank the families whose members have carried the burden of LD; without their cooperation this study would not have been possible. We also gratefully acknowledge the cooperation and assistance of Joan Spellman, Bernadette Sakamoto, and Susan G. Pietsch-Escueta, who helped recruit families and coordinate family studies. Our study was approved by the Human Subjects Protection Committee at the UCLA School of Medicine and the West Los Angeles DVA Medical Center. Each participating patient or, in the case of minors or deceased relatives, the responsible adult, signed an informed-consent form. Our project was supported by NIH-NINDS program project 5PO1-NS21908 (to A.V.D.-E.), by special contributions from Mrs. A. Malenfant and the Quebec Lafora's Disease Organization, and by Mrs. Vera Faludi of Sweden.

Gap junctions play a critical role in the metabolic homeostasis and maintenance of transparency of fibers within the ocular lens. As part of a long-term effort to establish the relationship between lens gap junction proteins, normal lens development, and cataractogenesis, we report here the regional localization of the human MP70 (Connexin 50) gene.Fluorescence in situ hybridization (FISH) was used to regionally map the human MP70 gene. The DNA probe contained the entire MP70 coding region within a clone isolated from a human genomic DNA library.The human gene encoding the lens intrinsic membrane protein MP70 was regionally mapped to q21.1 on the long arm of chromosome 1.This study confirms the previous provisional assignment of MP70 to human chromosome 1 and regionally localizes the gene to 1q21.1. When combined with previous mapping information, these data are consistent with the hypothesis that a genetic lesion in the gene encoding the lens intrinsic membrane protein MP70 may be the underlying molecular defect for zonular pulverulent (Coppock) cataract. Furthermore, these combined data support the hypothesis that other forms of human hereditary cataract may be the result of a mutation in one or more of the genes encoding gap junction proteins found in the ocular lens.

Juvenile myoclonic epilepsy is a common type of idiopathic generalized epilepsy characterized by myoclonic, generalized tonic‐clonic, and in 30% of patients, absence seizures. We studied a three‐generation pedigree of 33 members, 10 of whom were clinically affected with juvenile myoclonic epilepsy or presented with subclinical electroencephalographic (EEG) 3.5‐ to 6.0‐Hz diffuse polyspike‐wave or spike‐wave complexes. Juvenile myoclonic epilepsy and the EEG trait segregated as an autosomal dominant trait with 70% penetrance. Linkage analysis using this model showed significant linkage to four microsatellite markers centromeric to human leukocyte antigen (HLA) in chromosome 6p. Maximum lod scores of 3.43 at θ m=f = 0.00 for D6S272, D6S466, D6S257, and D6S402 were obtained. Recombinant events in 2 affected members defined the gene region to a 43‐cM interval flanked by D6S258 (HLA region) and D6S313 (centromere). Our results in this large family provide evidence that a gene responsible for juvenile myoclonic epilepsy and the subclinical, 3.5‐ to 6.0‐Hz, polyspike‐wave or spike‐wave EEG pattern is located in chromosome 6p.

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.

In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families.

The gene frequencies of nine different genetic polymorphic markers [ABO, MNS and P blood groups; haptoglobin, transferrin, Gc protein, complement (C3), properdin factor B and alpha(1)-antitrypsin] were determined in 94 Mexican-Americans residing in the Los Angeles, California area. Comparisons with published data on Mexican-Americans living in other areas of the United States or in Mexico itself revealed no significant differences in the gene frequencies between this and previous studies. However, data from the current study demonstrated significant differences in ABO and haptoglobin allele frequencies compared to published non-Hispanic Caucasian data. These data suggest a large degree of genetic homogeneity in the Mexican-American population residing in the United States. Additional gene marker studies will be important to test this hypothesis and further define the degree of non-Hispanic Caucasian admixture in this population.

The gene for the mouse recoverin protein (23 kDa photoreceptor‐specific protein, S‐modulin, or the Cancer‐Associated Retinopathy protein) was recently assigned to mouse chromosome 11, closely linked to trp53. In this paper, the human gene for recoverin was localized to human chromosome 17 by Southern analysis of restriction digests of the DNA from mouse/human somatic cell hybrids. Using a 7 kb subclone of the human recoverin gene, a positive fluorescence in situ hyridization signal was demonstrated near the terminus of the short arm of chromosome 17 at position p13.1. The mapping of recoverin to this region of human chromosome 17, which contains a number of cancer‐related loci, suggests a possible mechanism by which cancer‐associated retinopathy occurs in humans. © 1995 Wiley‐Liss, Inc.

Multiple human dihydrodiol dehydrogenases and human chlordecone reductase belong to the aldoketo reductase superfamily. These two enzymes are involved in the metabolism of xenobiotics, such as polycyclic aromatic hydrocarbons and pesticides. Recently we have isolated three closely related genes encoding two dihydrodiol dehydrogenases (DDH1 and DDH2) and the chlordecone reductase (CHDR). Mapping of the location of the genes was performed using the polymerase chain reaction using gene-specific primers to amplify gene sequences in human/hamster hybrid DNA. All three genes were found to be located on chromosome 10. In situ hybridization using a lambda clone as the probe further confirmed regional localization at 10p14–p15.

Despite affecting 4 million Americans and 100-200 million persons worldwide, the precise molecular mechanisms of human epilepsies remain unknown. Juvenile myoclonic epilepsy (JME) is the most frequent and, hence, most important form of hereditary grand mal epilepsy. In this epilepsy, electroencephalographic (EEG) 15-30-Hz multispikes produce myoclonic and tonic-clonic convulsions beginning at 8-20 years of age. Moreover, EEG 3.5-6-Hz multispike wave complexes appear in clinically asymptomatic family members. We first studied 38 members of a four-generation LA-Belize family with classical JME but with no pyknoleptic absences. Five living members had JME; four clinically asymptomatic members had EEG multispike wave complexes. Pairwise analysis tightly linked microsatellites centromeric to HLA, namely D6S272 (peak lod score [Zmax] = 3.564-3.560 at male-female recombination [theta m = f] = 0-.001) and D6S257 (Zmax = 3.672-3.6667 at theta m = f = 0-.001), spanning 7 cM, to convulsive seizures and EEG multispike wave complexes. A recombination between D6S276 and D6S273 in one affected member placed the JME locus within or below HLA. Pairwise, multipoint, and recombination analyses in this large family independently proved that a JME gene is located in chromosome 6p, centromeric to HLA. We next screened, with the same chromosome 6p21.2-p11 short tandem-repeat polymorphic markers, seven multiplex pedigrees with classic JME. When lod scores for small multiplex families are added to lod scores of the LA-Belize pedigree, Zmax values for D6S294 and D6S257 are > 7 (theta m = f = .000). Our results prove that in chromosome 6p21.2-p11 an epilepsy locus exists whose phenotype consists of classic JME with convulsions and/or EEG rapid multispike wave complexes.