Human 18 kDa phosphotyrosine protein phosphatase (ACP1) polymorphism: studies of rare variants provide evidence that substitutions within or near alternatively spliced exons affect splicing result

Abstract

The mammalian low molecular weight phosphotyrosine protein phosphatase is expressed as two distinct isoforms. The human ' fast ' and ' slow ' isoforms differ only in the sequence of an internal segment of 34 residues, and the ACP1 gene contains two adjacent exons (E3F and E3S) which encode these segments. We have previously suggested that the fast and slow isoforms are generated by mutually exclusive pre-mRNA splicing of E3F and E3S. The common alleles ACP1*A, *B and *C express the fast and slow isoforms in different ratios. The *A and *C alleles differ from *B by C 4 T transitions in E3S and E3F respectively. To test the idea that the fast : slow ratio is determined by nucleotide substitutions in the E3F-I3F-E3S region, four groups of rare ACP1 variants with unusual fast : slow ratios and the rare *E and *R alleles, expressing fast : slow ratios similar to *C and *B, respectively, were analysed. Gene segments of the I2-I3S region were amplified by PCR and analysed by SSCP and variant bands were excised and sequenced. For each of the rare isozymic variants one of six different nucleotide substitutions in E3F (ntsj42,j85,j109,j110), I3F (ntj1) and I3S (ntj8) was observed. The *E and *R alleles showed C and B sequence, respectively, in accordance with the fast : slow ratio. The results support the hypothesis that the fast : slow ratio is constitutive. 

Low-Molecular-Weight Protein Tyrosine Phosphatase Is a Positive Component of the Fibroblast Growth Factor Receptor Signaling Pathway

“…XLPTP1a and XLPTP1b differ from each other only in an internal 36-amino-acid region (positions 42 to 77) (Fig. 1b), suggesting that the two isoforms originate from alternative splicing (46,71).…”

“…Several isoforms of LMW-PTP have been identified in mammals and are believed to result from alternative splicing (18,19,46,50,53,78). These isoforms may have different kinetic characteristics and substrate specificities (15,71).…”

European ACP1*C Allele Has Recessive Deleterious Effects on Early Life Viability

“…These enzymes are identical, with the exception of 33 amino acids that are the products of the alternatively spliced third and fourth exons, respectively (Dissing and Johnsen 1992). Changes in the amount of F and S isozymes produced by each allele have been associated with mutations that interrupt exonic splicing enhancers (Rudbeck et al 2000). ACP1*C is the only allele to produce more S than F isozyme, and it also produces approximately six times more S isozyme (and somewhat less F isozyme) than any other major allele (Dissing 1987).…”

“…ACP1*C is the only allele to produce more S than F isozyme, and it also produces approximately six times more S isozyme (and somewhat less F isozyme) than any other major allele (Dissing 1987). These differences in isozyme production have been suggested to be the result of a single silent substitution in the third exon of ACP1*C that alters motifs recognized by human splicing factors SRp40 and SRp55 (Rudbeck et al 2000).Patterns of ACP1 allele frequency variation have been interpreted as evidence that particular genotypes may be adaptive in certain environments. This pattern is most striking for the ACP1*A and ACP1*B alleles.…”

ACP1 genotype, glutathione reductase activity, and riboflavin uptake affect cardiovascular risk in the obese

“…Erythrocyte acid phosphatase (ACP locus 1), also known as low-molecular-weight protein tyrosine phosphatase (LMW-PTP), has previously been associated to hyperglycemia, dyslipidemia, and obesity [1][2][3][4][5][6][7][8][9]. Recently, Pandey et al [4] demonstrated for the first time that ACP1 is a key negative regulator of insulin signaling in vivo.…”