Unexpected Linkage Research Articles

11q13 Allelotype Analysis in 27 Northern American MEN1 Kindreds Identifies Two Distinct Founder Chromosomes

We analyzed constitutional and tumor DNA from 27 MEN1 kindreds not known to be related to each other. Disease allele haplotypes were constructed for each pedigree based on shared alleles from two or more affected members and from determination of allelic loss patterns in their tumors. Analysis of disease allele haplotypes showed unexpected linkage disequilibrium at markerPYGM.Further haplotype analysis indicated this could be explained by the presence of two founder chromosomes, one in four families, the other in three. A shared disease haplotype was not observed among two MEN1 kindreds with the prolactinoma phenotype of MEN1.

Protein kinase C mediates activation of nuclear cAMP response element-binding protein (CREB) in B lymphocytes stimulated through surface Ig.

The cAMP response element-binding protein (CREB) is generally considered to be responsive to elevation of cAMP through the activity of protein kinase A (PKA). Although it is well known that cAMP-raising agents can strongly influence B cell stimulation, the regulation of CREB has been little studied. Recently, cross-linking of surface Ig (sIg) was shown to result in trans-activation of a cAMP response element (CRE)-dependent promoter to which bound B cell CREB. In this study, we explored the mechanism underlying this unexpected linkage between sIg and CREB. We found that sIg cross-linking results in phosphorylation of CREB at Ser133. Although this phosphorylation step is mediated by PKA in pheochromocytoma cells, it depends on protein kinase C (PKC) in B lymphocytes. This conclusion is based on abrogation of sIg-induced CREB Ser133 phosphorylation by long-term phorbol-ester treatment to deplete PKC, and mimicking of sIg-induced CREB phosphorylation and CRE-dependent gene expression by short-term PKC agonism. Furthermore, CD40 ligand (CD40L) and LPS, two PKC-independent forms of B cell stimulation, failed to induce phosphorylation of CREB Ser133. These results suggest that CREB responds to specific surface-receptor signals in B cells and that this response is mediated by PKC. Interestingly, forskolin failed to induce phosphorylation of CREB Ser133 in B cells, although it did so in PC12 pheochromocytoma cells. Taken together with PKC mediation of CREB Ser133 phosphorylation in B cells, these results suggest that the dominant mode of CREB regulation is cell-type specific.

Linkage of the acetylcholine transporter-vesamicol receptor to proteoglycan in synaptic vesicles.

The relationship of the acetylcholine transporter-vesamicol receptor (AcChT-VR) to proteoglycan in Torpedo electric organ synaptic vesicles was investigated. The cholate-solubilized VR was immunoprecipitated by a monoclonal antibody directed against the SV1 epitope located in the glycosaminoglycan portion of the proteoglycan. AcChT that was photoaffinity-labeled with a tritiated high-affinity analogue of AcCh [cyclohexylmethyl cis-N-(4-azidophenacyl)-N-methylisonipecotate] and then denatured in sodium dodecyl sulfate also immunoprecipitated. The labeled AcChT exhibited a M(r) range of 100,000-200,000. Proteoglycan did not engage in detectable nonspecific reversible aggregation that might mask the presence of another subunit during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In vesicles permeabilized with cholate, the enzymes keratanase and testicular hyaluronidase inactivated binding of vesamicol and destroyed the SV1 epitope without detectable proteolysis. Other glycosaminoglycan-degrading enzymes were without effect. The results demonstrate that the AcChT-VR and proteoglycan are very strongly linked and that glycosaminoglycan-like polysaccharide controls the conformation of the VR. The unexpected linkage to proteoglycan suggests that AcChT-VR in intact terminals might communicate with extracellular matrix and participate in stabilization and operation of the synapse.

The development of morphophonemic complexity in Eskimo languages

Abstract As I have recently argued (Fortescue, forthcoming 1992), the Eskimo-Aleut languages appear to have developed from an earlier, more agglutinative stage towards full-blown polysynthesis hand in hand with increasing mor-phophonemic complexity, the latter having today reached - especially in Alaskan Yupik - a daunting degree of complexity. I discuss there in “teleological” terms why this perhaps unexpected linkage might have come about without generalization of individual allomorphs having continually counteracted the complications resulting from normal phonological drift. The purpose of the present article is to sketch the route whereby this state of affairs was reached. The reconstruction is based upon the now virtually complete first version of the Comparative Eskimo Dictionary (Fortescue et al., forthcoming) and the recent comparative Eskimo-Aleut work by Knut Bergsland (especially Bergsland 1986 and 1989).

Detection of 14 HLA-DQB1 alleles by oligotyping

Fourteen alleles have been identified by analysis of the nucleotide sequences encoding the HLA-DQB1 chain. This study describes the detection of these 14 alleles by selective gene amplification and sequence-specific hybridization with nonradioactive oligonucleotide probes. These techniques were employed to create an oligotyping system with two levels of resolution that provide versatility and the capacity for comprehensive detection of all polymorphic sequences. An initial low-resolution assay was employed to detect four major groups of alleles that are associated with the DQw1-w4 serological specificities. A further high-resolution assay was then employed to differentiate 14 individual DQB1 alleles. Appropriate control measures were also included to detect carry-over and to confirm hybridization specificity. This system was used to analyze the allele frequencies of DQB1-0301, -0302, and -0303 in 115 DQB1-03 ∗∗ Caucasian blood donors. Allele frequencies of oligotypes DQB1-05 ∗∗ and DQB1-06 ∗∗ were analyzed in 112 DQB1-01 ∗∗ Caucasian blood donors. This system was also utilized to identify oligotypes designated DQB1-0501 through DQB1-0503 and DQB1-0601 through DQB1-0605 in 35 Tenth International Histocompatibility Workshop DQw1 cell lines to examine the correlation with serological and cellular specificities. In one of these cell lines, an unexpected linkage was discovered between the DRB1 and DQB1 loci, suggesting a recombination event. Oligotyping is a precise and accurate method for directly defining polymorphic sequences and it promises to have a major impact on the future direction of HLA typing.

Genetics of the peroxidase isoenzymes in Petunia

Three electrophoretic variants of the peroxidase b isoenzymes in Petunia have been found. The encoding gene prxB is shown to be located on chromosome I by its linkage with the gene Hfl. Analysis of prxB heterozygotes showed a gradual increase of the electrophoretic mobility of all three PRXb allozymes during development and differential expression in enzyme activity of three prxB alleles. The location of prxB on chromosome I was confirmed by an allelic dosage effect in trisomies I, trisomie segregation and the construction of trisomies I with triple-banded PRXb phenotype. From telotrisomic analysis it was concluded that prxB and Hfl are located on the same arm of chromosome I. The unexpected linkage of prxB and Hfl with the gene Fl in one of the crosses was suggested to be caused by a translocation in line SI, involving the gene Fl.

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