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PubMed1999

Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians.

High plasma concentrations of lipoprotein(a) [Lp(a)], a covalent low-density lipoprotein-apolipoprotein(a) [apo(a)] complex, are associated with coronary heart disease and stroke. Heritability of Lp(a) levels is high and the major locus determining Lp(a) concentrations is the apo(a) gene. We here demonstrate that a G-->A substitution at the +1 donor splice site of the apo(a) kringle (K) IV type 8 intron occurs with a high frequency ( approximately 6%) in Caucasians but not in Africans and is associated with congenital deficiency of Lp(a) in plasma. This mutation alone accounts for a quarter of all 'null' apo(a) alleles in Caucasians. RT-PCR analysis based on apo(a) illegitimate transcription in lympho- blastoid cells demonstrated that the donor splice site mutation results in an alternative splicing of the K IV type 8 intron and encodes a truncated form of apo(a). Expression of the alternatively spliced cDNA analogue in HepG2 cells showed that the truncated apo(a) form is secreted but is unable to form the covalent Lp(a) complex. Immunoprecipitated plasma apo(a) from homozygotes for the mutation was almost completely fragmented. Taken together, our data indicate that a failure in complex formation followed by fast degradation in plasma of the truncated free apo(a) is one mechanism which underlies the null Lp(a) type associated with the donor splice site mutation.

Alleles↗
PubMed2005

MHC-F DNA sequences in bonobo, gorilla and orangutan.

The major histocompatibility complex (MHC)-F class Ib locus shows a limited polymorphism, and the function of its mainly intracellular protein is not clear. We have identified human leucocyte antigen (HLA)-F orthologous DNA sequences in Pongidae in order to study the MHC-F gene evolution and its products' function. HLA-F orthologous cDNA transcripts are found in chimpanzee and in the new primate species studied (bonobo, gorilla and orangutan). Analyses of the predicted amino acid sequences and their comparison with other primate MHC-F proteins show that MHC-F may be a protein with a typical class I structure and that the key residues of the peptide-binding region (PBR) are highly conserved in MHC-F in all studied primates species. Thus, MHC-F conservation along the primate evolution suggests an important role in cellular physiology. It is possible that the MHC-F protein could be involved, together with MHC-G and MHC-E, in the natural killer (NK) cell activity regulation, although rhesus macaque does not express MHC-G and MHC-E orthologues. The evolutionary pathway of the six-base-pair deletion at exon 2 existing in some primates is put forward.

Amino Acid Sequence↗
PubMed2005

Rh proteins: key structural and functional components of the red cell membrane.

Rh (Rhesus) proteins (D, CcEe) are expressed in red cells (RBC) in association with other membrane proteins (RhAG, LW, CD47 and GPB). By interacting with the spectrin-based skeleton through protein 4.2 and ankyrin, the Rh complex contributes to the maintenance of the mechanical properties of the erythrocyte membrane. The RH system is one of the most immunogenic and polymorphic human blood group system. Molecular basis of most Rh phenotypes, including the Rh(null) phenotype associated with hemolytic anemia, have been determined. The demonstration that the RHD-positive locus is composed of the RHD and RHCE genes, whereas the RHD gene is deleted in most RhD-negative individuals, allowed fetal RhD genotyping by non-invasive PCR assays for antenatal diagnosis of pregnancy at risk for Rh hemolytic disease of the newborn. In mammals, the Rh protein family includes two non-erythroid members, RhBG and RhCG, mainly expressed in liver and kidney, two organs specialized in ammonia genesis and excretion. Functional analyses in heterologous systems revealed that RhAG, RhBG and RhCG can mediate ammonium (NH(3) and/or NH(4)(+)) transport across the cell membrane and might represent mammalian specific ammonium transporters. Furthermore, recent studies performed in human and murine red blood cells (RBC) indicate that RhAG facilitates CH(3)NH(2)/NH(3) movement across the membrane and represents a potential example of gas channel. The crystallographic structure of the bacterial ammonia channel AmtB and functional studies showing that AmtB conducts NH(3) into reconstituted vesicles is fully consistent with these latter studies. In RBCs, RhAG may transport NH(3) to detoxifying organs like kidney and liver and with non-erythroid tissues orthologs may contribute to regulation of the acid-base balance.

Ammonia↗
PubMed2004

Genetic dissection of embryo sac fertility, pollen fertility, and their contributions to spikelet fertility of intersubspecific hybrids in rice.

The partial sterility of hybrids has been a major barrier for utilization of the strong heterosis expressed in hybrids between Oryza sativa ssp. indica and O. sativa ssp. japonica. Wide-compatibility varieties, comprising a special class of germplasm, are able to produce fertile hybrids when crossed to both indica and japonica varieties. However, all the work on wide compatibility and majority of studies on indica/japonica hybrid sterility reported so far were based only on spikelet fertility; thus, it is not known to what extent male and female gamete abortions influence hybrid sterility. In this study, we investigated pollen fertility, embryo sac fertility, and spikelet fertility in an F1 population of 202 true hybrid plants derived from a three-way cross ('02428'/'Nanjing 11'//'Balilla'). A partial regression analysis showed that the pollen and embryo sac fertility contributed almost equally to spikelet fertility. QTL analysis based on a linkage map of 191 polymorphic marker loci identified two QTLs for pollen fertility, one QTL for embryo sac fertility, and three QTLs for spikelet fertility. The S5 locus, previously identified as a locus for wide compatibility by spikelet fertility analysis, is a major locus for embryo sac fertility, and a QTL on chromosome 5 had a major effect on pollen fertility. These two loci coincided with the two major QTLs for spikelet fertility. The study also detected a QTL on chromosome 8, showing a large effect on spikelet fertility but no effect on either pollen or embryo sac fertility. Very little interaction among the QTLs was detected. The implications of the findings in rice breeding programs are discussed.

Chromosome Mapping↗
PubMed2006

Congenic mice provide in vivo evidence for a genetic locus that modulates serum insulin-like growth factor-I and bone acquisition.

We identified quantitative trait loci (QTL) that determined the genetic variance in serum IGF-I through genome-wide scanning of mice derived from C57BL/6J(B6) x C3H/HeJ(C3H) intercrosses. One QTL (Igf1s2), on mouse chromosome 10 (Chr10), produces a 15% increase in serum IGF-I in B6C3 F2 mice carrying c3 alleles at that position. We constructed a congenic mouse, B6.C3H-10 (10T), by backcrossing c3 alleles from this 57-Mb region into B6 for 10 generations. 10T mice have higher serum and skeletal IGF-I, greater trabecular bone volume fraction, more trabeculae, and a higher number of osteoclasts at 16 wk, compared with B6 (P < 0.05). Nested congenic sublines generated from further backcrossing of 10T allowed for recombination and produced four smaller sublines with significantly increased serum IGF-I at 16 wk (i.e. 10-4, 10-7, 10-10, and 10-13), compared with B6 (P < 0.0003), and three smaller sublines that showed no differences in IGF-I vs. age- and gender-matched B6 mice. Like 10T, the 10-4 nested sublines at 16 wk had higher femoral mineral (P < 0.0001) and greater trabecular connectivity density with significantly more trabeculae than B6 (P < 0.01). Thus, by comprehensive phenotyping, we were able to narrow the QTL to an 18.3-Mb region containing approximately 148 genes, including Igf1 and Elk-3(ETS domain protein). Allelic differences in the Igf1s2 QTL produce a phenotype characterized by increased serum IGF-I and greater peak bone density. Congenic mice establish proof of concept of shared genetic determinants for both circulating IGF-I and bone acquisition.

Animals↗
PubMed2006

Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci.

Netrin signaling is important to guide migrating neurons and axons in many systems. Experiments with vertebrate CNS explants suggested netrin is bifunctional, attracting some axons and repelling others. Netrin1-expressing cells attracted spinal commissural axons and repelled trochlear cranial nerve axons in these experiments. Subsequent genetic studies demonstrated that multiple axon types, including those of the spinal commissural neurons, are attracted to netrin in vivo; however, an in vivo role for netrin signaling in trochlear nerve repulsion has not been observed. Here, we demonstrate that mice with a null mutation in the netrin receptor Unc5c on the inbred C57BL/6J (B6) genetic background have ventral/ipsilateral trochlear nerve misprojections. These misprojections are attenuated on a hybrid B6 x SJL background. In addition, B6.Unc5c(-/-) mice die as neonates of apparent respiratory distress and have incomplete phrenic nerve innervation of the diaphragm muscle. Neither the trochlear nerve misprojections nor the phrenic nerve phenotype was observed in B6 embryos lacking the netrin receptors DCC or Neogenin1, or the ligand netrin1, indicating these signaling molecules are dispensable for guidance of these axons. Like the trochlear nerve, the phrenic nerve phenotype is modified in a B6 x SJL hybrid background. To identify these modifier loci, we performed genome scans of the hybrid Unc5c(-/-) mice and found a major SJL-derived suppressor locus on Chromosome 17. Our results provide the first evidence that genes involved in netrin signaling are necessary for proper mammalian spinal motor axon development and trochlear axon guidance. In addition, they demonstrate the importance of modifier genes in vertebrate axonal guidance.

Animals↗
PubMed2005

Arrested natural killer cell development associated with transgene insertion into the Atf2 locus.

Natural killer (NK) cell development in the bone marrow is not fully understood. Following lineage commitment, these cells appear to advance through a series of developmental stages that are beginning to be characterized. We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1-specific inhibitory receptor driven by the granzyme A gene. This mouse has few NK cells in peripheral tissues with relative preservation of other immune cells, including T and B cells. Herein we demonstrate that these mice have an accumulation of NK cells with an immature phenotype in the bone marrow, consistent with a block at a previously proposed stage in normal NK-cell development. The phenotype is associated with transgenic insertion into Atf2, the gene for the basic leucine zipper (bZIP) transcription factor family member ATF-2. Although analysis of Atf2-null NK cells shows no defect, the transgenic mice express abnormal truncated Atf2 transcripts that may mediate a repressor effect because ATF2 can heterodimerize with other bZIP molecules. The defect is cell intrinsic, suggesting that certain bZIP molecules play significant roles in NK-cell development.

Activating Transcription Factor 2↗
PubMed2005

Role of resistant Drh1 locus in chemical carcinogen-induced hepatocarcinogenesis in rats: analysis with a speed congenic strain.

The DRH is an inbred rat strain established by selective mating of the 3'-Me-DAB resistant progeny of closed colony Donryu rats over 20 generations. Genetic analysis shows that two semidominant QTLs, Drh1 and Drh2, are responsible for strong resistance to chemical-induced hepatocarcinogenesis in DRH strain rats. To evaluate the effect of the single Drh1 locus on various stages of liver carcinogenesis, we constructed a speed congenic strain DRH.F344-Drh1 by transferring a susceptible Drh1 allele of F344 to DRH rats by marker-assisted backcrossing. The DRH.F344-Drh1 rats had a approximately 43 cM segment of chromosome 1 bearing Drh1 but the Drh2 was of the DRH allele. After oral administration of 3'-Me-DAB for 8 weeks, DRH.F344-Drh1 had as many enzyme altered foci as F344, whereas the quantitative parameters of fibrosis, enzyme altered foci, GST-P expression and proliferation of liver cells in DRH.F344-Drh1 rats were intermediate between F344 and DRH. In the liver of carcinogen-fed DRH rats, there was intensive apoptosis as detected by TUNEL stain, but not in the liver of F344 and DRH.F344-Drh1 rats. Injection of lead nitrate (100 micromol/kgB.W) induced a wave of liver cell proliferation, as seen by BrdU uptake within a few days in F344 and DRH.F344-Drh1 rats, but not in DRH rats. Instead, there were numerous TUNEL-positive nuclei in the DRH liver after lead nitrate injection. Apparently, the hepatocytes were removed by apoptosis during transition from G0 to G1. The major role of Drh1 is effective removal of the hepatocytes newly recruited to proliferate after chemical injury. Resistance to preneoplastic lesions in DRH rats may well be based on similar mechanism.

Administration, Oral↗
PubMed2005

FRIGIDA-independent variation in flowering time of natural Arabidopsis thaliana accessions.

FRIGIDA (FRI) and FLOWERING LOCUS C (FLC) are two genes that, unless plants are vernalized, greatly delay flowering time in Arabidopsis thaliana. Natural loss-of-function mutations in FRI cause the early flowering growth habits of many A. thaliana accessions. To quantify the variation among wild accessions due to FRI, and to identify additional genetic loci in wild accessions that influence flowering time, we surveyed the flowering times of 145 accessions in long-day photoperiods, with and without a 30-day vernalization treatment, and genotyped them for two common natural lesions in FRI. FRI is disrupted in at least 84 of the accessions, accounting for only approximately 40% of the flowering-time variation in long days. During efforts to dissect the causes for variation that are independent of known dysfunctional FRI alleles, we found new loss-of-function alleles in FLC, as well as late-flowering alleles that do not map to FRI or FLC. An FLC nonsense mutation was found in the early flowering Van-0 accession, which has otherwise functional FRI. In contrast, Lz-0 flowers late because of high levels of FLC expression, even though it has a deletion in FRI. Finally, eXtreme array mapping identified genomic regions linked to the vernalization-independent, late-flowering habit of Bur-0, which has an alternatively spliced FLC allele that behaves as a null allele.

Alternative Splicing↗
PubMed2006

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia.

The DYX2 locus on chromosome 6p22.2 is the most replicated region of linkage to developmental dyslexia (DD). Two candidate genes within this region have recently been implicated in the disorder: KIAA0319 and DCDC2. Variants within DCDC2 have shown association with DD in a US and a German sample. However, when we genotyped these specific variants in two large, independent UK samples, we obtained only weak, inconsistent evidence for their involvement in DD. Having previously found evidence that variation in the KIAA0319 gene confers susceptibility to DD, we sought to refine this genetic association by genotyping 36 additional SNPs in the gene. Nine SNPs, predominantly clustered around the first exon, showed the most significant association with DD in one or both UK samples, including rs3212236 in the 5' flanking region (P = 0.00003) and rs761100 in intron 1 (P = 0.0004). We have thus refined the region of association with developmental dyslexia to putative regulatory sequences around the first exon of the KIAA0319 gene, supporting the presence of functional mutations that could affect gene expression. Our data also suggests a possible interaction between KIAA0319 and DCDC2, which requires further testing.

5' Untranslated Regions↗
PubMed2005

Subtle sequence variation among MHC class I locus products greatly influences sensitivity to HCMV US2- and US11-mediated degradation.

Human cytomegalovirus (HCMV) interferes with cellular immune responses by modulating surface expression of MHC class I molecules. Here, we focused on HCMV-encoded unique short (US) 2 and US11, which bind newly synthesized MHC class I heavy chains (HCs) and support their dislocation into the cytosol for subsequent degradation by proteasomes. Not all MHC class I locus products are equally sensitive to this down-modulation. The aim of this study was to identify which domains, and ultimately which residues, are responsible for the resistance or sensitivity of MHC class I molecules to US2- and US11-mediated down-regulation. We show that, besides endoplasmic reticulum-lumenal regions, the C-terminus of class I molecules represents an important determinant for allele specificity in US11-mediated degradation. HLA-E becomes sensitive to US11-mediated down-regulation when its cytoplasmic tail is extended. Interestingly, this only requires two additional residues, lysine and valine, at its C-terminus. For US2, the MHC class I allele specificity is largely determined by a small region at the junction of the alpha2/alpha3 domain of the HC. It is quite remarkable that minor changes, in only four residues, can completely revert the sensitivity of naturally US2-resistant HLA-E molecules. With this study we provide better insights into the features underlying the selectivity in MHC class I down-regulation by US2 and US11.

Alleles↗
PubMed1997

Molecular genetics of the renin-angiotensin-aldosterone system in human hypertension.

Blood pressure is a quantitative trait that varies along a continuum in the general population and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Family studies and twin studies suggest that about 30% of blood pressure variance is attributable to genetic factors and 50% to environmental factors. Two forms of hypertension transmitted on an autosomal recessive basis have been identified: one is glucocorticoid-suppressible hyperaldosteronism (GSH) and the other is Liddle's syndrome (amiloride-suppressible hyperactivity of the epithelial sodium channel). The molecular basis for these two forms of severe hypertension has recently been elucidated. GSH is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. Apart from these rare genetic defects, a number of susceptibility genes can increase the risk of hypertension in a given environment. Their presence is neither necessary nor sufficient to cause hypertension. The best documented example is the angiotensinogen gene. Angiotensiongen is the substrate of renin, and the renin-angiotensinogen reaction is the first and limiting step in the pathway that leads to production of angiotensin II, a peptide with important effects on blood pressure control and the metabolism of water and sodium. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension or hypertension of pregnancy. The M235T variant of angiotensinogen is more prevalent among hypertensive than among normotensive subjects in several Caucasian and Japanese populations. The M235T variant is also associated with plasma angiotensinogen elevation, which is potentially responsible for increased production of angiotensin II. In other terms, relationships exist between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distal phenomenon (i.e., blood pressure elevation). DNA libraries for the study of hypertension have been set up, and many informative genetic markers distributed along the genome have been identified. Using position cloning techniques, these markers could be used in the search for genetic links between arterial hypertension and a chromosomal locus.

Angiotensinogen↗
PubMed2005

Identification of a new class of pistil-specific proteins of Petunia inflata that is structurally similar to, but functionally distinct from, the self-incompatibility factor HT.

Pollen-pistil interactions are thought to involve a wide variety of intercellular recognition events controlled by diverse proteins and other molecules. One of the best characterized interactions is the S-RNase-based gametophytic self-incompatibility (GSI) system found in Solanaceae, Rosaceae and Scrophulariaceae. Although the S specificity of the pistil and the pollen in these families is determined by the S locus-encoded proteins S-RNase and SLF/SFB, respectively, these proteins alone are not sufficient for operation of the GSI reaction. Other factors are also required and are classified into three groups. To date, the only known factor is the pistil-expressed small asparagine-rich protein HT-B in three solanaceous genera Nicotiana, Lycopersicon and Solanum. HT-B is a Group 2 factor that is required for pollen rejection but do not affect S-RNase expression; factors in the other groups have not yet cloned. Here, we identified a new class of HT-like proteins in the style of Petunia inflata and named it HTL. Through alternative splicing, it was found that two isolated homologous HTL cDNAs, HTL-A and HTL-B, derived from a single gene. Like HT-B, HTL showed pistil-specific accumulation as well as significant sequence similarity to HT including conserved cystein residues at the C-terminal region and a signal peptide for extracellular localization. However, unlike HT-B, HTL lacked an asparagine-rich domain. Thus, it represents a new class of HT proteins. To determine whether HTL is involved in GSI function, RNA silencing constructs for HTL-A and HTL-B were introduced into self-incompatible P. inflata. Although several transgenic lines showed no detectable levels of both HTL-A and HTL-B transcripts, they retained normal GSI function and produced large fruits upon compatible pollination. This suggests that since silencing of the HTL gene alone is not sufficient to affect reproductive physiology, the gene is functionally distinct from the GSI factor HT-B.

Flowers↗
PubMed2002

Simultaneous improvement for four quality traits of Zhenshan 97, an elite parent of hybrid rice, by molecular marker-assisted selection.

"Zhenshan 97" is the female parent of a number of widely used hybrids for rice production in China. However, this line is of poor quality because of a high amylose content (AC), a hard gel consistency (GC) and a low gelatinization temperature (GT), together with a chalky endosperm. It had been determined that the three traits for cooking and eating quality, AC, GC and GT, are controlled by the Waxy locus and/or the tightly linked genomic region. In this study we improved the eating and cooking quality of Zhenshan 97 by introgressing the Waxy gene region from Minghui 63 (wx-MH), a restorer line, that has medium AC, soft GC and high GT. The wx-MH fragment was transferred to Zhenshan 97B by three backcrosses and one selfing, then from Zhenshan 97B to Zhenshan 97A by a cross and a backcross. Molecular marker-assisted selection was applied in the series to select for individuals carrying wx-MH, to identify recombination between the Waxy and flanking markers, and also to recover the genetic background of the recurrent parent. According to the marker genotypes, the improved versions of Zhenshan 97B and Zhenshan 97A, or Zhenshan 97B(wx-MH) and Zhenshan 97A(wx-MH), were the same as the originals except for the Waxy region of less than 6.1 cM in length. The selected lines and their hybrids with Minghui 63, or Shanyou 63(wx-MH), showed a reduced AC and an increased GC and GT, coupled with a reduced grain opacity. Field examinations of agronomic performance revealed that Zhenshan 97B(wx-MH) and Shanyou 63(wx-MH) were essentially the same as the originals except for a significant decrease in grain weight. The simultaneous improvement of AC, GA, GT and opacity, indicated that the Waxy region had major effects on the four quality traits. The improved versions of Zhenshan 97 A and B should be immediately useful in hybrid rice production.

Amylose↗
PubMed2006

Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19.

Evidence from four independent linkage studies and two meta-analyses of genome-wide data support the existence of a locus conferring susceptibility to inflammatory bowel diseases (IBD) in chromosomal region 19p. Identification of a susceptibility allele in this approximately 28.5 Mb region with over 600 genes is a formidable task. To tackle this problem, we undertook two approaches: (1) haplotype-based candidate-gene screen, and (2) evaluation of previously reported associations. For the former, we selected genes with potential implication in IBD pathogenesis based on published functional and expression data, typed SNPs, constructed haplotypes, screened for association in 180 IBD trios, and followed up preliminary associations in 343 IBD patients and 207 control individuals. Overall, we analyzed 465 SNPs, and 260 haplotypes distributed across 56 candidate genes. We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up. In the second approach, we typed four nonsynonymous polymorphisms in genes C3 (R102G and L314P) and ICAM1 (G241R and K469E) in four independent cohorts totaling 2178 IBD cases. We evaluated these data together with previously published reports for three of these variants (C3-Gly102, ICAM1-Arg241, and ICAM1-Glu469), in a meta-analysis. Our pooled meta-analysis provides compelling evidence against association of these variants with disease. Overall, we performed the most comprehensive candidate-gene association study for IBD to date. The information hereby generated constitutes a valuable resource to investigate other common genetic immune diseases, such as celiac disease.

Alleles↗
PubMed2006

Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation.

OBJECTIVE: c-jun N-terminal kinase (JNK) has been implicated in proliferation and survival downstream from the tyrosine kinase oncogene, p210 BCR-ABL, in chronic myeloid leukemia. We studied whether a similar relationship between JNK and FMS-like tyrosine kinase 3 (Flt3) describes acute myeloid leukemia (AML). METHODS: By immunoprecipitation, Flt3 was found to be activated and identified as the potential origin of JNK activity in a heavy majority of JNK+ve AML blasts tested. Often, Flt3 activity is associated with activating mutation of the gene locus. However, statistical linkage tied JNK activity with Flt3 expression levels rather than with mutation. An adaptor network to describe the signal cascade Flt3-to-JNK was uncovered. RESULTS: Active Flt3 was linked to p85 phosphoinositide-3 (PI-3) kinase, and p85 with cbl and CrkII/CrkL by co-immunoprecipitaton assays from lysates of model cell lines and primary AML blasts. JNK1 co-immunoprecipitated from such lysates with p85-cbl-crkII/L and bound to Crk species SH3 domain in pull-down assay. siRNA-mediated depletion of Flt3 or of cbl, the adaptor at the nexus of this signaling group, inhibited JNK activity on substrate c-jun. Within AML blast cells influenced by Flt3 signaling, selective inhibition of JNK by a small molecule inhibitor, led to proliferative inhibition, apoptosis, and sensitizing cells to the anthracycline, daunorubicin. These effects occurred upon JNK inhibition without off-target inhibition of extracellular signal-regulated kinase or AKT pathways, and p38-kinase activation, an effector in the p53/p14 arf tumor suppressor pathway, was also maintained or augmented. CONCLUSION: JNK is a bonafide signaling pathway from Flt3 in AML whose function for proliferation and survival is required in a significant AML cohort with active Flt3 signaling, by mutation or overexpression of Flt3.

Apoptosis↗
PubMed2006

Identification of a novel A1v-O1v hybrid allele with G829A mutation in a chimeric individual of AelBel phenotype.

BACKGROUND: Many A and B suballeles responsible for ABO subgroup formation have been identified. Some of these minor alleles have mutations in the ABO gene coding sequence. Most of these mutations are due to single-nucleotide substitution and lead to amino acid alteration. Several alleles at the ABO locus appear to be caused by crossing over between dissimilar alleles. STUDY DESIGN AND METHODS: Blood samples were collected from an individual with AelBel phenotype and her family members. Sequencing of the seven ABO exons was performed on these samples. The following was performed for the samples from the AelBel proposita: cloning and sequencing of the genomic DNA of the ABO gene, reverse transcription-polymerase chain reaction (PCR) analysis of cDNA transcript of the ABO gene, sequence-specific priming (SSP)-PCR analysis and direct sequencing of the ABO gene, SSP-PCR DNA typing of generic HLA-ABC and HLA-DRB, and short-tandem repeat (STR)-PCR typing on 15 autosomal, 2 X-chromosomal, and 6 Y-chromosomal loci. RESULTS: The proposita with AelBel phenotype has blood group chimerism with a major group of A1v-O1v/O1(O01) and a minor group of B(B101)/O1v(O02). Additional haplotypes on HLA-ABC, HLA-DR-B, STR loci, and Y-chromosome STR loci were present on the proposita. The paternal genotype is B(B101)/O1(O01) and the maternal genotype is A1v(A102)/O1v(O02). No other siblings have the A1v-O1v hybrid allele. Parentage was confirmed with the paternity STR-PCR test. Full-length cDNA transcripts of the B(B101) allele and alternately spliced cDNA transcripts of the hybrid A1v-O1v, O(1), and O1v alleles were cloned from the proposita. The A1v-O1v hybrid gene contains two missense mutations: C467T and G829A, resulting in Pro156Leu and Val277Met substitution. CONCLUSION: Formation of the A1v-O1v hybrid allele appears to result from de novo recombination in the germ line of the mother during meiosis. G829A with Val277Met appears to be responsible for the decrease in A-transferase activity and Ael phenotypic expression in the proposita. The chimeric minor population of B(B101)/O1v is responsible for Bel phenotypic expression in the proposita.

ABO Blood-Group System↗