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Biomedical subjects

A E Bale

Publications and source records attributed to A E Bale.

At least 73 records · Page 4Linked to original sources
PubMed1991

A contiguous linkage map of chromosome 13q with 39 distinct loci separated on average by 5.1 centimorgans.

A fine-structure linkage map of chromosome 13q is presented. This map contains 39 continuously linked loci defined by genotypes generated from the CEPH family DNAs with 56 probe and enzyme combinations. An alpha-satellite probe for sequences on chromosome 13 was included, resulting in a complete map of 13q with 39 distinct loci. The map spans 1.715 M in males and 2.099 M in females and the mean genetic distance between adjacent loci is 5.1 cM. Although there was generally a several-fold excess of female recombination in the interstitial portion of 13q, an excess of recombination in males was observed at both ends of this chromosomal arm. This map should be useful for the localization of any additional marker, gene, or disease locus of interest on chromosome 13q.

Chromosome Mapping↗
PubMed1991

Localization of CYP2F1 by multipoint linkage analysis and pulsed-field gel electrophoresis.

CYP2F1, which encodes a P450 enzyme capable of metabolizing several mono-oxygenase substrates with the highest activity toward ethoxycoumarin, has been mapped to human chromosome 19 by somatic cell hybrid studies. The CYP2A and CYP2B subfamilies are known to lie within 350 kb of each other on chromosome 19. To determine the locations of CYP2F1 with respect to CYP2A and CYP2B, multipoint linkage analysis and pulsed-field gel electrophoresis were performed. No recombinants were found between CYP2F1 and CYP2B in more than 50 meioses, and one recombinant was found between CYP2F1 and CYP2A (50 meioses). Pulsed-field gel electrophoresis showed the three loci to lie within a 240-kb region. Multipoint analysis of the haplotyped CYP cluster with four other chromosome 19 loci yielded the order D19S7-D19S9-APOC2-D19S8-CYP, although four other orders could not be excluded. The odds were 4.4 x 10(3) against the order proposed by the HGM10 consortium, D19S7-D19S9-CYP-D19S8-APOC2.

Chromosome Mapping↗
PubMed1991

A new point mutation in the 3,5,3'-triiodothyronine-binding domain of the c-erbA beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance.

Two different mutations in the c-erbA beta thyroid hormone receptor have recently been reported as genetic abnormalities responsible for the syndrome of generalized thyroid hormone resistance (GTHR). We have now found in a third kindred, D, in which GTHR is inherited as a dominant disease, a new point mutation in the T3-binding domain of c-erbA beta. A guanine to cytosine base substitution at nucleotide position 1305, which altered codon-335 from glutamine (CAG) to histidine (CAC), was found in one allele of 10 affected members and was not found in 6 unaffected members. This C-1305 sequence was not present in 106 random alleles, indicating that it was a mutation in c-erbA beta, and it was tightly linked to GTHR in kindred D, with a maximum logarithm of the odds score of 4.19 at a recombination fraction of 0. The tight linkage result confirms that GTHR maps to the c-erbA beta locus in multiple kindreds. In view of the tight linkage between the C-1305 mutation and GTHR, and that this mutation is a nonconservative alteration in a crucial region of the T3-binding domain, it is probably the genetic defect in kindred D responsible for GTHR. The kindred D receptor appears to result in a different phenotype of tissue resistance compared to the previously reported kindred. A receptor with a mutation in the carboxy-terminus of c-erbA beta.

Base Sequence↗
PubMed1991

Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP.

The human CYP1A1 (cytochrome P1450) gene encodes an enzyme involved in the activation of procarcinogens, such as benzo[a]pyrene, to the ultimate reactive intermediate. Approximately 10% of the human population exhibit high CYP1A1 inducibility, and Kouri et al. reported that the high-inducibility phenotype might be at greater risk than low-inducibility individuals for cigarette smoke-induced bronchogenic carcinoma. In one 3-generation family of 15 individuals, we show here that the high-CYP1A1-inducibility phenotype segregates concordantly with an infrequent polymorphic site located 450 bases downstream from the CYP1A1 gene. Our findings are consistent with the study of Kawajiri et al., who demonstrated an association between this polymorphism and an increased incidence of squamous-cell lung cancer. Our data suggest that the CYP1A1 structural gene, or a region near this gene, might be correlated with the inducibility phenotype.

Cells, Cultured↗
PubMed1990

A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds.

Generalized thyroid hormone resistance (GTHR) is a disorder of thyroid hormone action that we have previously shown to be tightly linked to one of the two thyroid hormone receptor genes, c-erbA beta, in a single kindred, A. We now show that in two other kindreds, B and D, with differing phenotypes, there is also linkage between c-erbA beta and GTHR. The combined maximum logarithm of the odds score for all three kindreds at a recombination fraction of 0 was 5.77. In vivo studies had shown a triiodothyronine (T3)-binding affinity abnormality in nuclear receptors of kindred A, and we therefore investigated the defect in c-erbA beta in this kindred by sequencing a major portion of the T3-binding domain in the 3'-region of fibroblast c-erbA beta cDNA and leukocyte c-erbA beta genomic DNA. A base substitution, cytosine to adenine, was found at cDNA position 1643 which altered the proline codon at position 448 to a histidine. By allelic-specific hybridization, this base substitution was found in only one allele of seven affected members, and not found in 10 unaffected members of kindred A, as expected for a dominant disease. Also, this altered base was not found in kindreds B or D, or in 92 random c-erbA beta alleles. These results and the fact that the mutation is predicted to alter the secondary structure of the crucial T3-binding domain of the c-erbA beta receptor suggest this mutation is an excellent candidate for the genetic cause of GTHR in kindred A. Different mutations in the c-erbA beta gene are likely responsible for the variant phenotypes of thyroid hormone resistance in kindreds B and D.

Alleles↗
PubMed1990

Analysis of gonadotropin-releasing hormone gene structure in families with familial central precocious puberty and idiopathic hypogonadotropic hypogonadism.

We examined the GnRH gene structure in a family with familial central precocious puberty (eight members, four affected) and a family with idiopathic hypogonadotropic hypogonadism (eight members, three affected) using Southern blot analysis and sequencing of cloned polymerase chain reaction products. Genomic DNA samples were digested with restriction enzymes and hybridized to the human placental GnRH cDNA probe. BamHI digests revealed 6.5- and 2.7-kilobase (kb) bands; BglII, 6.0- and 4.0-kb bands; Ncol, 8.0- and 3.5-kb bands; Pstl, 4.2-kb, 2.8-kb, 1.3-kb and 950-basepair bands; XbaI, 6.5- and 5.0-kb bands. These sizes were the same as those found by this analysis in normal individuals. All family members with familial central precocious puberty or idiopathic hypogonadotropic hypogonadism showed the same size bands, except for one unaffected member of the family with idiopathic hypogonadotropic hypogonadism who had an additional band at 5.5 kb after digestion with NcoI, which is thought to be a rare polymorphism. Sequencing of exon 2 of the GnRH gene from these families, including the exon-intron borders, revealed a polymorphism in the signal sequence of GnRH that predicts an amino acid change from tryptophan (nucleotide sequence: TGG) to serine (TCG) at the -8 position of the GnRH preprohormone. Although this polymorphism did not cosegregate with the clinical disorder in either family, this novel polymorphism may prove useful in the evaluation of linkage to the GnRH gene in other families with pubertal disorders. No other nucleotide sequence abnormality was found in 1.2 kb of the 5' flanking region or the four exons and their splice sites.

Adult↗
PubMed1990

Genetic abnormalities in sporadic parathyroid adenomas.

We analyzed genomic DNA from 43 sporadic benign parathyroid adenomas for rearrangements of the PTH gene, and for point mutations of the H-ras (codons 12, 13, and 61), N-ras (codons 12, 13, and 61), and K-ras (codons 12 and 13) genes. One of 43 parathyroid adenomas showed a chromosome 11 rearrangement involving both the PTH gene on the short arm of chromosome 11 (at band p15) and a locus on the long arm (11q13). This rearrangement was indistinguishable from one that was previously described in a parathyroid adenoma by Arnold et al., indicating that this may be an important contributor to tumorigenesis in a small subset of patients with parathyroid adenoma. H-ras, K-ras, and N-ras oncogene activation by point mutation at codons 12, 13, or 61, known to occur in many tumors, could not be detected in any parathyroid adenoma.

Adenoma↗
PubMed1990

A locus for familial hypertrophic cardiomyopathy is closely linked to the cardiac myosin heavy chain genes, CRI-L436, and CRI-L329 on chromosome 14 at q11-q12.

We report that a gene responsible for familial hypertrophic cardiomyopathy (HC) is closely linked to the cardiac alpha and beta myosin heavy chain (MHC) genes on chromosome 14q11. We have recently shown that probe CRI-L436, derived from the anonymous DNA locus D14S26, detects a polymorphic restriction fragment that segregates with familial HC in affected members of a large Canadian family. Using chromosomal in situ hybridization, we have mapped CRI-L436 to chromosome 14 at q11-q12. Because the cardiac MHC genes also map to this chromosomal band, we have determined the genetic distances between the cardiac beta MHC gene, D14S26, and the familial HC locus. Data presented here show that these three loci are linked within 5 centimorgans on chromosome 14 at q11-q12. The possibility that defects in either the cardiac alpha or beta MHC genes are responsible for familial HC is discussed.

Cardiomyopathy, Hypertrophic↗
PubMed1989

Sister chromatid exchange and chromosome fragility in the nevoid basal cell carcinoma syndrome.

Previous studies of chromosome stability in the nevoid basal cell carcinoma syndrome have yielded inconsistent results and suffered from small sample sizes and less than optimal controls. We investigated chromosome fragility and sister chromatid exchange in 20 affected individuals from five multiplex pedigrees, and 15 first- or second-degree unaffected relatives. The percentage of case and control cells showing breaks or rearrangements was compared using a test of proportions. A similar procedure was used to compare site-specific sister chromatid exchanges in baseline cultures from affected persons and controls. No significant differences were noted for either chromosome fragility or sister chromatid exchange between the two groups. These results suggest that cancer susceptibility in the nevoid basal cell carcinoma syndrome is not caused by or manifested as chromosome instability.

4-Nitroquinoline-1-oxide↗
PubMed1989

Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1.

Familial multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, endocrine pancreas, and anterior pituitary. Since the gene associated with MEN-1, located on chromosome 11 (11q13), may normally inhibit tumor proliferation, tumors could arise from inactivation of one or both of the alleles. However, parathyroid tumors in patients with MEN-1 have been considered to result from polyclonal hyperplasia. Using genetic probes, we tested parathyroid tumors for a monoclonal component, represented by a loss of alleles at any of eight loci along chromosome 11. Ten of 16 tumors from 14 patients with familial MEN-1 had losses of alleles from chromosome 11. Tumors with losses were larger than those without (1.6 vs. 0.2 g; P less than 0.002), suggesting that a monoclonal adenoma may develop after a phase of polyclonal hyperplasia. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included one copy of the MEN-1 locus. Of 34 sporadic adenomas from patients without MEN-1, 9 showed similar allelic losses in chromosome 11; in 7 the losses included the apparent MEN-1 locus. We conclude that many "hyperplastic" parathyroid tumors in familial MEN-1 are in fact monoclonal and may progress or even begin to develop by inactivation of the MEN-1 gene (at 11q13) in a precursor cell. Some sporadic adenomas have allelic losses on chromosome 11, which may also involve the MEN-1 gene.

Adenoma↗
PubMed1989

Linkage analysis of multiple endocrine neoplasia type 1 with INT2 and other markers on chromosome 11.

We evaluated linkage between the locus for multiple endocrine neoplasia type 1 (MEN1) and several polymorphic DNA markers on chromosome 11 in a single large pedigree. On the basis of the finding of a basic fibroblast growth factor (bFGF)-like substance circulating in plasma of MEN1 patients, we chose a bFGF-related gene known to be localized to 11q13 as one of the markers. This gene locus, INT2, was found to be closely linked to the MEN1 gene. Pairwise and multipoint analyses with INT2 confirm the recent finding by C. Larsson et al. (1988, Nature (London) 332: 85-87) of MEN1 linkage to another marker, skeletal muscle glycogen phosphorylase, at 11q13.

Chromosomes, Human, Pair 11↗
PubMed1988

Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene.

Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T3 with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies have suggested quantitative or qualitative defects in T3 binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA alpha and c-erbA beta, we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbA beta locus on chromosome 3. This linkage strongly suggests that the c-erbA beta gene is important in man as a thyroid hormone receptor and identifies a putative c-erbA beta mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.

Drug Resistance↗
PubMed1987

Linkage analysis in spinopontine atrophy: correlation of HLA linkage with phenotypic findings in hereditary ataxia.

Because linkage has been reported between HLA and the locus for hereditary ataxia in some families, we studied a 3-generation kindred in which several individuals had dominantly inherited spinopontine atrophy. Affected family members had upper and lower limb ataxia, hypoactive reflexes, loss of proprioception, dysarthria, dysphagia, and pronounced extraocular movement abnormalities. Linkage analysis, based on 25 markers in 28 people, gave strongly negative results with both HLA (z less than -2.0 for theta less than 0.15) and GLO1 (z less than -2.0, theta less than or equal to 0.01). The highest LOD score was for linkage to GPT on chromosome 16 (z = 0.42, theta = 0.0). To assess the relationship between HLA linkage and phenotype, 4 published kindreds with adequate clinical and neuropathological descriptions were used for comparison to the present family. Persons in the 3 families showing evidence for HLA linkage had clinical and pathologic changes consistent with olivopontocerebellar atrophy, type 1. The conditions in the 2 "nonlinked" families were phenotypically distinct from the HLA-linked condition with respect to extraocular movement findings and peripheral sensory nervous system signs. They differed markedly from each other in neuropathologic changes.

Adult↗