No abstract

CD45 is a receptor-type protein tyrosine phosphatase involved in the regulation of lymphocyte activation. Different CD45 isoforms are generated by alternative splicing of three variable exons (A, B and C). The pattern of CD45 splicing depends upon cell type and state of activation. CD45RA isoforms (containing exon A-encoded sequences) can usually be found on a subset of resting T cells, but not on activated T cells. We have recently described a variant pattern of CD45RA expression which is characterized by continuous expression of CD45RA molecules on activated and memory T cells. Here, we demonstrate that this phenotype is associated with heterozygosity for a point mutation at nucleotide position 77 of exon A, leading to a C-->G transition. This mutation does not change the protein sequence of the CD45RA isoform. We conclude that position 77 is part of a motif necessary for splicing of exon A, which supports the hypothesis that sequences within exons have significant effects on alternative splicing. The mutation of this motif might prevent binding of a transacting splice factor. In the heterozygous state, this mutation is not associated with impaired T cell reactivity. Functional consequences of the homozygous state remain to be elucidated.

No abstract

To assess the development, stability, and clinical relevance of donor-type microchimerism, skin and blood were analyzed in heart (n = 53) and liver (n = 18) transplant recipients by nested polymerase chain reaction. Microchimerism was detectable in 40 (75%) and 13 (72%) patients after heart and liver transplantation, respectively. In heart transplantation, chimerism-positive patients showed a lower frequency of acute rejection as compared with negative patients, although this was only of borderline statistical significance. Repeated intraindividual analyses demonstrated variable patterns of microchimerism over time, but changes did not correlate to the clinical state. In liver transplantation, chimeric state showed no clear correlation with the patients' immunological situation. Our results demonstrate that peripheral microchimerism frequently develops after different types of organ transplantation and represents a dynamic process but without diagnostic value to predict the immunological risk for individual patients.

No abstract

We have analyzed the CTG repeat length and the neighboring A/u insertion/deletion [+/-) polymorphism in DNA samples from 16 ethnically and geographically diverse human populations to understand the evolutionary dynamics of the myotonic dystrophy-associated CTG repeat. Our results show that the CTG repeat length is variable in human populations. Although the (CTG}5 repeat is the most common allele in the majority of populations, this allele is absent among Costa Ricans and New Guinea highlanders. We have detected a IZCTG} 4 repeat allele, the smallest CTG known allele, in an American Samoan individual. {CTG}~I9 alleles are the most frequent in Europeans followed by the populations of Asian origin and are absent or rare in Africans. To understand the evolution of CTG repeats, we have used haplotype data from the CTG repeat and Alu{+l-} locus. Our results are consistent with previous studies, which show that among individuals of Caucasian and Japanese origin, the association of the A/u[+} allele with CTG repeats of 5 and I>19 is complete, whereas the A/ulZ-} allele is associated with {CTG}~I_~6 repeats. However, these associations are not exclusive in non-Caucasian populations. Most significantly, we have detected the (CTG} s repeat allele on an A/u{-} background in several populations including Native Africans. As no (CTG}s repeat allele on an A/u[-~] background was observed thus far, it was proposed that the A/uC-~] allele arose on a (CTG}vH3 background. Our data now suggest that the most parsimonious evolutionary model is [I} {CTG}5-A/uI~+} is the ancestral haplotype; {2} (CTG}s-A/u[-} arose from a I~CTG}s-A/u(+} chromosome later in evolution; and [3} expansion of CTG alleles occurred from {CTG}s alleles on both A/u(+} and A/u[-~] backgrounds.Myotonic dystrophy (DM), one of the most common neuromuscular genetic disorders in adults, is characterized by myotonia accompanied by progressive weakness and wasting of distal muscles, cataracts, and cardiac arrhythmias (Harper 1989). It became the third example of human genetic disorders associated with trinucleotide repeat expansion when a normally polymorphic CTG repeat (5-37 repeats in normal individuals) located in the 3' untranslated region (UTR) of the myotonin protein kinase gene (DMPK) on 19q13.3 was found to be unstable and massively expanded (from 50 to several thousand repeats)

Microsatellite polymorphisms of nine Eurasian populations (> 1200 chromosomes) were analyzed for the following loci: i) intronic (gt)n stretches of three T cell receptor (TCR) B loci on chromosome 7 (TCRBV6S1, TCRBV6S3, TCRBV6S7); ii) an intergenic (gt)n repeat in the region between the TCRDV3 and TCRAJ61 elements on chromosome 14; iii) two tetranucleotide simple repeats (D12S66, D12S67), not linked to known genes on chromosome 12; iv) a Y-chromosomal (gata)n polymorphism (DYS19). In general, allele frequencies and heterozygosity rates were similar, but specific alleles were missing in one or more populations. Distinct DYS19 alleles predominated in particular cohorts. Different allele frequencies were observed for the TCR loci in European and Asian populations. Tetranucleotide polymorphisms were distributed normally, whereas TCR alleles displayed bimodal frequency profiles. For TCRBV6S1 and TCRBV6S7, this profile reflects a diallelic protein polymorphism that correlates exactly with the length of the intronic repeats.

A point mutation in exon A (C to G transversion at position 77) of human PTPRC (CD45) has recently been associated with the development of multiple sclerosis (MS) for at least a subgroup of patients. In the present report, we studied the frequency of the 77C-->G transversion in two other autoimmune diseases namely systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The mutation was found with significantly enhanced frequency in patients suffering from SSc suggesting that PTPRC could play a role as susceptibility gene not only in MS but also in other autoimmune diseases. Further understanding of the mode of interaction of mutant PTPRC with other susceptibility genes may uncover mechanisms common in various autoimmune disorders.