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PubMed2006

Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo.

Activation of JAK2 by chromosomal translocation or point mutation is a recurrent event in hematopoietic malignancies, including acute leukemias and myeloproliferative disorders. Although the effects of activated JAK2 signaling have been examined in cell lines and murine models, the functional consequences of deregulated JAK2 in the context of human hematopoietic cells are currently unknown. Here we report that expression of TEL-JAK2, a constitutively active variant of the JAK2 kinase, in lineage-depleted human umbilical cord blood cells results in erythropoietin-independent erythroid differentiation in vitro and induces the rapid development of myelofibrosis in an in vivo NOD/SCID xenotransplantation assay. These studies provide functional evidence that activated JAK2 signaling in primitive human hematopoietic cells is sufficient to drive key processes implicated in the pathophysiology of polycythemia vera and idiopathic myelofibrosis. Furthermore, they describe an in vivo model of myelofibrosis initiated with primary cells, highlighting the utility of the NOD/SCID xenotransplant system for the development of experimental models of human hematopoietic malignancies.

Animals↗
PubMedDate not supplied

Epidemiologic findings in congenital anemia, dyserythropoiesis, and dyskeratosis in polled Hereford calves.

Congenital dyserythropoiesis and dyskeratosis occur within certain lines of Polled Hereford cattle. Eighty-nine of 90 alleles in 45 affected calves had a mechanism in which they could be identical by descent from an identified common ancestor. The line allele may have been a recurrence of the mutation, or the mutation may have occurred earlier in the breed's history and been distributed throughout the breed by the extensive use of several ancestors. No evidence of disease has been identified in sire and dams of affected calves, suggesting that the allele is not acting in a dominant or incompletely dominant manner. Even distribution of cases between sexes suggests that the disease is not sex linked or sex influenced. A higher degree of inbreeding in the affected calves and temporal and spatial features that separated individual cases also suggest a genetic cause. Segregation ratios were not significantly different from those of the hypothesized simple autosomal recessive inheritance.

Anemia, Dyserythropoietic, Congenital↗
PubMed2006

Terminal B cell differentiation is skewed by deregulated interleukin-6 secretion in beta2 integrin-deficient mice.

Absence of the common beta chain (CD18) of beta(2) integrins leads to leukocyte-adhesion deficiency type-1 (LAD1) in humans. Mice with a CD18 null mutation suffer from recurrent bacterial infections, impaired wound healing, and skin ulcers, closely resembling human LAD1. Previous findings in CD18(-/-) mice demonstrated a skewed terminal B cell differentiation with plasmacytosis and elevated serum immunoglobulin G (IgG). As interleukin-6 (IL-6) is a potent enhancer of plasma cell formation and Ig secretion, we assessed IL-6 serum levels of CD18(-/-) and wild-type (WT) mice kept under a conventional or barrier facility or specific pathogen-free (SPF) conditions. We detected an up to 20-fold increase in IL-6 in serum of CD18(-/-) mice compared with WT controls when kept under conventional or barrier facility conditions, respectively. Under SPF conditions, no significant differences in terms of IL-6 serum levels were found between CD18(-/-) and WT mice. However, histological alterations of secondary lymphoid tissues, plasmacytosis, abnormal plasmacytoid cells (Mott cells), and hypergammaglobulinemia persisted. To further analyze the role of IL-6 in these pathological alterations, we established a CD18(-/-) IL-6(-/-) double-deficient mouse mutant. In these mice, serum IgG levels were normal, and the altered plasma cell phenotype, including Mott cells, was no longer detectable. The CD18(-/-) IL-6(-/-) double-deficient mouse model thus demonstrated that IL-6 is responsible for parts of the phenotype seen in the CD18(-/-) mouse mutants. It may be of interest to examine human leukocyte-adhesion deficiency type-1 patients closer and search for pathological changes possibly induced via overproduction of IL-6.

Animals↗
PubMed2006

Genotyping of five chinese patients with 17alpha-hydroxylase deficiency diagnosed through high-performance liquid chromatography serum adrenal profile: identification of two novel CYP17 mutations.

CONTEXT: 17alpha-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia caused by CYP17 gene mutations. OBJECTIVE: Five Chinese patients with 17alpha-hydroxylase deficiency were genotyped. PATIENTS: The five patients derived from four families living in Shandong Province, China. The diagnosis of 17alpha-hydroxylase deficiency was initially established through HPLC serum adrenal profiles in Qilu Hospital, China, from 1983-1993. RESULTS: Three CYP17 gene mutations were identified from these patients. Among them, V311fs and Y329fs are two novel frame-shifting mutations. V311fs is an 8-bp nucleotide (TTAAATGG) deletion in exon 5. Y329fs is a deletion-insertion combined mutation (TAC-->AA) at codon 329 in exon 6. Two homozygotes for Y329fs and one compound heterozygote for Y329fs and V311fs were identified from three different families. Two homozygous sisters for the D487_S488_F489 deletion were identified. CONCLUSION: The results confirmed the diagnostic value of the HPLC serum adrenal profile for 17alpha-hydroxylase deficiency. The D487_S488_F489 deletion had been identified in two previously genotyped Chinese families. In our present study, a third Chinese family with this mutation was identified, suggesting that this mutation is a prevalent CYP17 mutation in the Chinese population. The identification of Y329fs mutation in addition to three previously identified mutations at codon 329 suggests that codon 329 is an unstable point of the CYP17 gene. The mutations identified from our five patients appear to be random, but the recurrence of the Y329fs mutation may be attributed to a founder effect. Our studies suggest that 17alpha-hydroxylase deficiency may not be rare in the Chinese population.

Adolescent↗
PubMed2004

Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder in humans that is characterised by multisystemic vascular dyplasia and recurrent haemorrhage. Germline mutations in one of two different genes, endoglin or ALK1 can cause HHT. Both are members of the transforming growth factor (TGF) beta receptor family of proteins, and are expressed primarily on the surface of endothelial cells (ECs). Mice that lack endoglin or activin receptor like kinase (ALK) 1 die at mid-gestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFbeta signalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFbeta type II receptor (TbetaRII) or ALK5. We show that TGFbeta/ALK5 signalling from endothelial cells to adjacent mesothelial cells is defective in these mice, as evidenced by reduced phosphorylation of Smad2. This results in the failure of vascular smooth muscle cells to differentiate and associate with endothelial cells so that blood vessels remain fragile and become dilated. Phosphorylation of Smad2 and differentiation of smooth muscle can be rescued by culture of the yolk sac with exogenous TGFbeta1. Our data show that disruption of TGFbeta signalling in vascular endothelial cells results in reduced availability of TGFbeta1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.

Activin Receptors, Type I↗
PubMed2026

Detection of House Dust Mite-derived DNA in Human Lung Tumors by Whole-Genome Sequencing.

Lung cancer in never-smokers (LCINS) accounts for an increasing proportion of lung cancer cases, yet its risk factors remain poorly understood. House dust mites (HDM) are common aeroallergens that induce airway inflammation, but their potential contribution to lung cancer is unknown. We analyzed unmapped whole-genome sequencing reads from 783 lung cancers from the Sherlock-Lung (n = 621 never-smokers) and EAGLE (n = 162 smokers) cohorts, including 328 matched adjacent normal lung tissues. After removal of human sequences, reads were aligned to reference genomes from the two major HDM species and confirmed by BLAST. Samples with top BLAST matches were classified as HDM-detected. Associations between HDM detection and genomic, microbiome, and bulk RNA-seq-derived immune features were evaluated. HDM-derived DNA was detected at low abundance in a subset of tumors and adjacent normal tissues, with higher detection frequencies in tumors than matched normal tissues and in smokers than never-smokers. In LCINS tumors, HDM detection was not associated with tumor mutational burden or recurrent driver alterations but was associated with modest differences in immune cell composition and a limited but reproducible bacterial co-detection pattern. These findings provide a foundation for investigating aeroallergen-derived DNA signatures and their potential relationship to the lung tumor microenvironment.

Environmental exposure↗
PubMed2026

Integrated Immunotherapy Target Atlas for Ewing Sarcoma.

BACKGROUND/AIM: Ewing sarcoma is a fusion-driven malignancy with low tumor mutational burden, making recurrent tumor-associated antigens with favorable tumor-to-normal contrast central to immunotherapy development. We converted the Deng et al.-defined 32-gene Ewing Sarcoma Specific Signature (ESS32) into a practical target atlas by integrating tumor RNA expression with normal-tissue context, protein evidence, subcellular localization, and therapeutic accessibility. MATERIALS AND METHODS: A 38-gene set was analyzed, including ESS32 and six comparator antigens (STEAP1, LINGO1, PRAME, CD99, CD276/B7-H3, and ENPP1). Eight Gene Expression Omnibus datasets (n=854 samples) were assigned predefined roles spanning tumor-versus-skeletal-muscle comparison, broad normal-organ context, EWSR1::FLI1 perturbation, tumor-only support cohorts, cell-line models, and cross-sarcoma comparison. Results were overlaid with Human Protein Atlas and published proteomic/surfaceome evidence. RESULTS: In GSE17674, the strongest tumor-enriched transcripts included NKX2-2, NPY1R, STEAP1, RBM11, RNF182, LIPI, CD99, STEAP2, LOXHD1, and DCDC2. Normal-tissue and compartment data substantially reordered RNA-only ranking. NKX2-2 showed the strongest Ewing-associated signal but encodes a nuclear transcription factor, favoring peptide-HLA/T-cell receptor (TCR) or vaccine development. RBM11 and LIPI emerged as high-interest intracellular/secretome-associated candidates, with an explicit epididymal/male reproductive caveat for LIPI. CD99 and NPY1R illustrated normal-cell reservoir and receptor-distribution constraints. CONCLUSION: ESS32 should be interpreted as an EWSR1::FLI1-associated RNA discovery set, not as a pre-validated target panel. Practical nomination requires integration of RNA enrichment, normal-tissue distribution, protein evidence, cellular compartment, and modality compatibility before nomination of TCR, vaccine, antibody-drug conjugate (ADC), chimeric antigen receptor (CAR), radioligand, or validation-first candidates.

Humans↗
PubMed2005

AML1-ETO needs a partner: new insights into the pathogenesis of t(8;21) leukemia.

The detailed characterization of genetic and molecular aberrations in acute myeloid leukemia (AML) has substantially improved our understanding of the pathogenesis of this disease. With an incidence of up to 12% in all AML cases, the translocation t(8;21), forming the AML1-ETO fusion gene, is one of the most common genetic aberrations in AML. Experimental data have shown that AML1-ETO is not sufficient to induce leukemia by itself, but has to collaborate with other genetic alterations for leukemic transformation. These data are supported by observations in AML patients, who recurrently show activating mutations of the receptor tyrosine kinase FLT3 or c-KIT together with the AML1-ETO fusion gene. These findings might have clinical implications and provide a rationale to test RTK inhibitors in the treatment of patients with core binding factor AML and concurrent activating RTK mutations.

Chromosomes, Human, Pair 21↗
PubMed2006

Functional characterization of SLC7A9 polymorphisms assumed to influence the cystinuria phenotype.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3-A1 gene cause type I cystinuria, patients with non-type I cystinuria mostly carry mutations in the SLC7A9 gene. However, there is evidence that further genetic factors cause and influence the cystinuria phenotype. We recently demonstrated that specific polymorphisms in Exons 3, 4, 5 and 6 of the SLC7A9 gene show a significant different allelic distribution between cystinuria patients and controls. To determine the role of the variants in these exons we transfected COS7 cells with expression constructs containing different haplotypes. Sequencing of cDNAs derived from the resulting SLC7A9 mRNAs did not reveal any differences in expression between the minigenes of the specific haplotypes. Our findings suggest that the variants in SLC7A9 do not influence splicing behavior. Thus, the reasons for the different allelic distribution between cystinuria patients and controls remain unclear. It is conceivable that this distribution is caused by the association of certain alleles with so far undetected mutations in the gene.

Amino Acid Transport Systems, Basic↗
PubMed2002

[Expression and mutation of c-kit gene in gastrointestinal stromal tumor].

OBJECTIVE: To investigate the effect of the expression and mutation of c-kit gene and its relationship with clinical pathology and prognosis of gastrointestinal stromal tumor (GIST). METHODS: Immunohistochemical and PCR-SSCP techniques were used to detect c-kit protein expression and c-kit gene exon 11 mutation in 82 patients with GIST. RESULTS: The positive c-kit protein expression and c-kit gene mutation rates were 97.6% (80/82) and 41.5% (34/82). Correlating the results of these two methods and clinicopathological factors, the c-kit expression and c-kit gene mutation rates were 95.0% (19/20) and 0 in benign GIST, and were 98.4% (61/62), 54.8% (34/62) in malignant GIST. Mutation positive GIST showed higher frequency of adjacent tissue invasion, metastasis and recurrence as compared with mutation negative ones. CONCLUSION: c-kit protein is an important diagnostic marker of gastrointestinal stromal tumor. c-kit gene mutation may play a significant role in the pathogenesis of GIST and also may be a prognostic marker.

Adolescent↗
PubMed2003

Genetic variations of the SLC7A9 gene: allele distribution of 13 polymorphic sites in German cystinuria patients and controls.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3A1 gene cause type I cystinuria, patients with non-type I cystinuria carry mutations in the SLC7A9 gene. Both gene products form the renal amino acid transporter rBAT/b0,+AT affected in cystinuria. In the present study a total of 59 patients with different ethnic background were screened for sequence variations in SLC7A9, out of these 32 were of German origin. For determination of allele frequencies of detected polymorphisms, 58 healthy German controls were investigated. Molecular-genetic analysis was performed using single-strand conformation polymorphism analysis, restriction assays and sequencing. Allele frequencies were analyzed statistically for the detected polymorphisms. In addition to the 6 already known variants we identified 7 new polymorphisms. Statistical analyses showed a significantly different distribution of alleles between German patients and German controls in case of the polymorphisms c. 147C>T (exon 2), c.386C>T (exon 3), IVS3+22T>G, c.584C>T (exon 4), c.610T>C (exon 4), c.692C>T (exon 5), c.852C>A (exon 6) and c.872C>T (exon 6). In summary, our results show that cystinuria is a complex disease which is not only caused by mutations in SLC7A9 and SLC3A1, but also influenced by other modifying factors such as variants in SLC7A9.

Alleles↗
PubMed1998

[XY gonadal dysgenesis (Swyer syndrome) with gonadoblastoma].

This is a case report of 46 xy gonadal dysgenesis (Swyer-syndrome) with bilateral androgen producing gonadoblastoma in streak gonads in a 15-year-old patient. The presenting features were: hypergonadotrophic hypogonadism, male pseudohermaphroditism and virilisation. A hypoplastic uterus with normal looking Fallopian tubes and bilateral adnexal tumors were detected through laparoscopy. A laparotomy was performed and the streak gonads with bilateral gonadoblastoma were removed. This led to a normalisation of serum testosterone and serum beta-HCG levels and an amelioration of signs of virilisation. Uterus and fallopian tubes were conserved during the operation. A second look laparoscopy 6 months later showed no evidence of recurrent tumor. No mutation were found in the sex-determining gene (SRY) on DNA-screening using SSCP assay.

Adolescent↗
PubMed2001

The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation.

The G20210A mutation in the prothrombin gene is associated with an increased risk of a first venous thromboembolic episode; few data are available about the long-term risk for recurrent venous thromboembolism and it is not known whether or not carriers of the mutation should be recommended lifelong anticoagulant treatment after the first thrombosis. We investigated 624 patients, referred for previous objectively documented deep venous thrombosis of the legs or pulmonary embolism, to determine the risk of recurrent thromboembolism in heterozygous carriers of the G20210A mutation in the prothrombin gene after the first episode of venous thromboembolism. After exclusion of other inherited (anti-thrombin, protein C, protein S deficiency and factor V Leiden) or acquired (anti-phospholipid antibody syndrome) causes of thrombophilia, 52 heterozygous carriers of the prothrombin mutation were compared with 283 patients with normal genotype. The relative risk for recurrent venous thromboembolism was calculated between groups using a Cox's proportional hazard model. The patients with the prothrombin mutation had a risk for spontaneous recurrent venous thromboembolism similar to that of patients with normal genotype (hazard ratio 1.3; 95% CI, 0.7-2.3). The circumstances of the first event (spontaneous or secondary) did not produce any substantial variation in the risk for recurrence. In conclusion, the carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype.

Adolescent↗
PubMed1997

K-ras mutations in patients with early colorectal cancers.

BACKGROUND: Published data are contradictory about the importance of K-ras mutations in advanced tumours and are not available for early cancers. AIMS: To establish whether specific K-ras mutations are prognostic markers in early stage colorectal adenocarcinoma. METHODS: The presence of K-ras exon 1 mutations were correlated with tumour recurrence in two groups of patients: group 1 was a consecutive series of patients with resected colorectal adenocarcinoma at low risk of recurrence; group 2 were patients referred for chemotherapy after relapse of previously resected early stage tumours. K-ras mutations were detected by direct sequencing of whole tissue samples in all patients and in some, the leading edge and centre of the tumour were also microdissected out individually and sequenced. RESULTS: Mutations were present in 26 (26.5%) of 98 patients in group 1; 14 patients developed a recurrence, four (28.5%) of whom had a K-ras mutation. Seventy nine patients have not developed tumour recurrence, 22 (28%) of whom had a mutation (p = 0.84). K-ras mutations were present in five of 14 patients in group 2. Microdissection did not increase the number of mutations detected. CONCLUSIONS: Individual K-ras genotypes are distributed homogeneously throughout early stage colorectal adenocarcinomas, but detection of a mutation has no apparent prognostic value.

Adenocarcinoma↗
PubMed1994

Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase.

We have previously reported that greater than 60% of human leukemic T-cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 "paired" T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild-type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice.

Base Sequence↗
PubMed1999

The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.

BACKGROUND: Point mutations in the factor V gene (factor V Leiden) and the prothrombin gene (the substitution of A for G at position 20210) are the most common causes of inherited thrombophilia. Whether or not factor V Leiden increases the risk of recurrent deep venous thrombosis is controversial, and there is no information on the risk of recurrence among carriers of both mutations. METHODS: We studied a retrospective cohort of 624 patients who were referred for a first episode of deep venous thrombosis. After excluding 212 patients with other inherited or acquired causes of thrombophilia, we compared 112 patients who were heterozygous carriers of factor V Leiden with 17 patients who were heterozygous for both factor V Leiden and the prothrombin mutation and 283 patients who had neither mutation. The relative risk of recurrent deep venous thrombosis was calculated with use of a proportional-hazards model. RESULTS: Patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.6; P=0.76). In contrast, patients who were heterozygous for both factor V Leiden and the prothrombin mutation had a higher risk of recurrent thrombosis than did carriers of factor V Leiden alone (relative risk, 2.6; 95 percent confidence interval, 1.3 to 5.1; P=0.002). When the analysis was restricted to patients with spontaneous recurrences (i.e., ones that occurred in the absence of transient risk factors for venous thrombosis), the risk among carriers of both mutations, as compared with carriers of factor V Leiden alone, remained high (relative risk, 3.7; 95 percent confidence interval, 1.7 to 7.7; P<0.001), particularly if the first event had also been spontaneous (relative risk, 5.4; 95 percent confidence interval, 2.0 to 14.1; P<0.001). In contrast, the risk of recurrence in the presence of transient risk factors was similar among carriers of both mutations and carriers of factor V Leiden alone. CONCLUSIONS: The risk of recurrent deep venous thrombosis is similar among carriers of factor V Leiden and patients without this mutation. Carriers of both factor V Leiden and the G20210A prothrombin mutation have an increased risk of recurrent deep venous thrombosis after a first episode and are candidates for lifelong anticoagulation.

Adolescent↗
PubMed1995

Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene.

Mutations in the human aldolase B gene that result in hereditary fructose intolerance have been characterized extensively. Although the majority of subjects have been from northern Europe, subjects from other geographical regions and ethnic groups have been identified. At present 21 mutations have been reported; 15 of these are single base substitutions, resulting in nine amino acid replacements, four nonsense codons, and two putative splicing defects. Two large deletions, two four-base deletions, a single-base deletion, and a seven-base deletion/one-base insertion have been found. This last mutation leads to a defect in splicing and it is likely that one of the small deletions does as well. Regions of the enzyme where mutations have been observed recurrently are encoded by exons 5 and 9. Indeed, the three most common mutations are found in these exons. Two of these prevalent HFI mutations arose from a common ancestor and spread throughout the population by genetic drift. This finding was based on linkage to two sequence polymorphisms, which are among very few informative polymorphic markers that have been identified within the aldolase B gene. Because of the prevalence of a few HFI alleles, and the recent advances in molecular methods for identifying and screening for mutation, the diagnosis of HFI by molecular screening methods should become routine. These molecular diagnostic methods will be extremely beneficial for this often difficult to diagnose and sometimes fatal disease.

Chromosome Mapping↗
PubMed2003

Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: associations with recurrent pregnancy loss.

Our specific aim was to assess associations of thrombophilia, hypofibrinolysis, and polycystic ovary syndrome (PCOS) with recurrent pregnancy loss (RPL) (>/=3 consecutive pregnancy losses < 20 weeks gestation). Prospective studies were performed in 33 Caucasian women referred for diagnosis and treatment of PCOS who were subsequently found to have RPL and in 16 Caucasian women referred for diagnosis and treatment of RPL, who did not have PCOS. Cases (PCOS-RPL, RPL without PCOS) were compared with controls (116 healthy Caucasian females) for the G1691A Factor V Leiden, G20210A prothrombin, C677T methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor 4G/5G, and platelet glycoprotein PL A1A2 gene mutations. Cases were compared with controls (44 healthy adult Caucasian females) for serologic coagulation tests including homocysteine, proteins C, S, free S, antithrombin III, anticardiolipin antibodies IgG and IgM, dilute Russel's viper venom time, activated partial thromboplastin time, Factor VIII, Factor XI, lipoprotein (Lp)(a), and plasminogen activator inhibitor activity (PAI-Fx). The 33 Caucasian women with PCOS subsequently found to have RPL were 10% of a cohort of 322 Caucasian women who had >/= 1 previous pregnancy and had been referred for diagnosis and therapy of PCOS over a 4.3-year period. The Factor V Leiden G1691 mutation was present in 6 of 33 women (18%) with PCOS-RPL and in 3 of 16 women with RPL without PCOS (19%) versus 2 of 116 (1.7%) female controls, Fisher's P (p(f)) =.0016, p(f) =.013. The 33 PCOS-RPL cases also differed from the 44 female controls for high PAI-Fx (>21.1 U/mL), 38% versus 8%, p(f) =. 004. The thrombophilic G1691A Factor V Leiden mutation is associated with RPL in women with and without PCOS; hypofibrinolysis (high PAI-Fx) is also associated with RPL in women with PCOS.

Abortion, Spontaneous↗