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PubMed2005

Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction.

Although previous epidemiologic studies have suggested an association between the onset of myocardial infarction (MI) and some genetic variations, the impact of these variants on recurrent cardiovascular events after MI has not been fully elucidated. We genotyped 87 polymorphisms of 73 atherosclerosis-related genes in consecutive acute MI patients registered in the Osaka Acute Coronary Insufficiency Study and compared the incidence of death and major adverse cardiac events (MACE) among the polymorphisms of each gene. After initial screening in 507 patients, we selected nine polymorphisms for screening in all 1586 patients. Multivariate Cox regression analysis revealed that G allele carriers at the position 252 of the lymphotoxin alpha (LTA) gene were independently associated with an increased risk of death (hazard ratio [HR]: 2.46; 95% CI: 1.24-4.86). In conclusion, a 252G allele of LTA is associated with an increased risk of death after AMI and may be a useful genetic predictor.

Atherosclerosis↗
PubMed1999

Focal loss of CD44 variant protein expression is related to recurrence in superficial bladder carcinoma.

The majority of papillary transitional cell carcinomas of the bladder are localized tumors at initial diagnosis; identification of those developing recurrence and an aggressive behavior is important. CD44 variant proteins have been implicated in tumor progression and metastasis, and a correlation with adverse prognosis has been demonstrated in a variety of human tumors. Here, the usefulness of conventional CD44 protein immunohistochemistry as a prognostic parameter for recurrence of superficial transitional cell carcinomas was assessed in paraffin sections of 241 tumors with long-term follow-up. A highly significant association was found between focal loss of CD44v3 and -v6 immunostaining and short recurrence-free interval in noninvasive (pTa) transitional cell carcinomas (P = 0.005), but not in minimally invasive (pT1) carcinomas (P = 0.78). Our results indicate the value of conventional CD44 immunohistochemistry as an additional tool for identifying patients at high risk for recurrence of pTa transitional cell carcinomas. They also point to biological differences between noninvasive and minimally invasive transitional cell carcinomas of the bladder.

Carcinoma, Transitional Cell↗
PubMed2000

Clinical and laboratory expression of associated thrombophilic conditions (homozygous/heterozygous factor V Leiden mutation and heterozygous prothrombin variant 20210A) in an Italian family.

Prothrombin variant 20210A is maintained to be a mild risk factor for venous thromboembolism (VTE). The association of this defect with other inherited thrombophilic conditions may result in an increased risk of developing VTE. In this article, a family is described in which prothrombin variant was associated with either homozygous or heterozygous factor V Leiden (FV Leiden) mutation. All family members except the proband were asymptomatic despite the presence and the severity of the underlying genetic defect(s). The proband, who carried homozygous FV Leiden mutation and heterozygous prothrombin variant, experienced recurrent VTE during pregnancies, whereas one brother, with the same defect, was asymptomatic. Mean prothrombin antigen and activity levels were higher in carriers of the prothrombin variant as compared with noncarriers. Thrombin generation was assessed in family members, in carriers of prothrombin variant or homozygous FV Leiden mutation and in a control group. Most of the family members presented with increased prothrombin fragment 1+2 levels possibly because of the presence of the FV Leiden mutation. Although it is conceivable that the co-inheritance of prothrombin variant and FV Leiden mutation may increase the risk of VTE, patients with these combined defects may remain asymptomatic. It is likely that acquired triggering conditions play a major role in determining VTE in carriers of a mild genetic predisposition. This has to be taken into account when recommendation for thromboprophylaxis is given.

Adolescent↗
PubMed2025

Estimation of demography and mutation rates from one million haploid genomes.

As genetic sequencing costs have plummeted, datasets with sizes previously unthinkable have begun to appear. Such datasets present opportunities to learn about evolutionary history, particularly via rare alleles that record the very recent past. However, beyond the computational challenges inherent in the analysis of many large-scale datasets, large population-genetic datasets present theoretical problems. In particular, the majority of population-genetic tools require the assumption that each mutant allele in the sample is the result of a single mutation (the "infinite-sites" assumption), which is violated in large samples. Here, we present DR EVIL, a method for estimating mutation rates and recent demographic history from very large samples. DR EVIL avoids the infinite-sites assumption by using a diffusion approximation to a branching-process model with recurrent mutation. This approach results in tractable likelihoods that are accurate for rare alleles. We show that DR EVIL performs well in simulations and apply it to rare-variant data from one million haploid samples. We identify mutation-rate heterogeneity even after accounting for trinucleotide context and methylation status. We also predict that at modern sample sizes, the alleles at most polymorphic sites with high mutation rates represent the descendants of multiple mutation events.

Haploidy↗
PubMed1978

Mitral-valve prolapse syndrome and recurrent ventricular tachyarrhythmias: a malignant variant refractory to conventional drug therapy.

Of 60 patients referred for management of drug-refractory ventricular tachyarrhythmias, 10 (17%) had mitral-valve prolapse. These 10 patients ranged in age from 19 to 70 years (mean, 47 years); seven were women. All 10 had recurrent ventricular tachycardia, while four had a history of ventricular fibrillation. Nine patients were refractory to propranolol in combination with one or more of the standard antiarrhythmic agents. All showed improvement with aprindine therapy. The results show that refractory malignant ventricular prolapse syndrome; patients with mitral-valve prolapse account for a rather high percentage of those patients referred with recurrent drug-refractory ventricular tachyarrhythmias; in patients with unexplained ventricular arrhythmias, mitral-valve prolapse should be considered; and aprindine may be effective for ventricular tachyarrhythmias associated with mitral-valve prolapse.

Adult↗
PubMed2023

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

BACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown. METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy. RESULTS: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells. CONCLUSION: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.

Animals↗
PubMed1990

Hypermutability of CpG dinucleotides in the propeptide-encoding sequence of the human albumin gene.

An electrophoretically slow albumin variant was detected with a phenotype frequency of about 1:1000 in Sweden and was also found in a family of Scottish descent from Kaikoura, New Zealand, and in five families in Tradate, Italy. Structural study established that the major variant component was arginyl-albumin, in which arginine at the -1 position of the propeptide is still attached to the processed albumin. A minor component with the amino-terminal sequence of proalbumin was also present as 3-6% of the total albumin. After amplification of the gene segment encoding the prepro sequence of albumin, specific hybridization of DNA to an oligonucleotide probe encoding cysteine at position -2 indicated the mutation of arginine at the -2 position to cysteine (-2 Arg----Cys). This produced the propeptide sequence Arg-Gly-Val-Phe-Cys-Arg. This was confirmed by sequence analysis after pyridylethylation of the cysteine. This mutation produces an alternate signal peptidase cleavage site in the variant proalbumin precursor of arginyl-albumin giving rise to two possible products, arginyl-albumin and the variant proalbumin. Another plasma from Bremen had an alloalbumin with a previously described substitution (1 Asp----Val), which also affects propeptide cleavage. Hypermutability of two CpG dinucleotides in the codons for the diarginyl sequence may account for the frequency of mutations in the propeptide. Mutation at these two sites results in a series of recurrent proalbumin variants that have arisen independently in diverse populations.

Amino Acid Sequence↗
PubMed1994

Cellular benign fibrous histiocytoma. Clinicopathologic analysis of 74 cases of a distinctive variant of cutaneous fibrous histiocytoma with frequent recurrence.

We report seventy-four cases of a distinctive variant of cutaneous fibrous histiocytoma, which is often mistaken histologically for sarcoma and which carries a high local recurrence rate. These tumors appeared most commonly in young or middle-aged adults, with a predominance in men (male/female ratio 1.9:1). Anatomic distribution was wide, with cases occurring mainly in the upper limb/limb girdle (34%), lower limb/limb girdle (27%), and head and neck region (20%). Most lesions had been present for only a few months, and their sizes ranged from 0.5 cm to 2.5 cm in maximum diameter. Twelve (26%) of 46 cases with follow-up (mean duration 3 years) recurred locally, in one case twice. Distinctive histologic features were a commonly fascicular growth pattern, predominance of eosinophilic spindle cells with tapering nuclei, a moderate mitotic rate (mean three per 10 high-power fields), and frequent extension into the subcutaneous fat (33% of cases). In addition, all cases showed at least focal cytologic polymorphism (inflammatory cells, foam cells, giant cells), and 58% showed associated epidermal alterations in common with usual cutaneous fibrous histiocytomas. Nine cases (12%) showed foci of central necrosis. Immunohistochemical studies (ABC method) found only vimentin and very focal smooth muscle actin positivity. Tests for CD34, desmin, S-100, keratin, and Factor XIIIa were negative in all cases. These lesions should be distinguished from dermatofibrosarcoma protuberans and leiomyosarcoma, with which many of these cases were initially confused.

Adolescent↗
PubMed1994

Recurrent pyogenic granuloma with satellitosis--a localized variant of bacillary angiomatosis?

A 27-year-old male patient had recurrent pyogenic granuloma with satellitosis. Histologically, Warthin-Starry staining of the lesions revealed clumps of dark bacilli as found in patients with bacillary angiomatosis. IgG antibodies against Bartonella (Rochalimaea) henselae were elevated as shown by an indirect immunofluorescence assay. The patient did not present an obvious risk for HIV infection or immunosuppression, and no antibodies against HIV-1 and HIV-2 were found. Recurrent pyogenic granuloma with satellitosis may be a localized variant of bacillary angiomatosis.

Adult↗
PubMed2005

The G protein-coupled receptors: pharmacogenetics and disease.

Genetic variation in G-protein coupled receptors (GPCRs) is associated with a wide spectrum of disease phenotypes and predispositions that are of special significance because they are the targets of therapeutic agents. Each variant provides an opportunity to understand receptor function that complements a plethora of available in vitro data elucidating the pharmacology of the GPCRs. For example, discrete portions of the proximal tail of the dopamine D1 receptor have been discovered, in vitro, that may be involved in desensitization, recycling and trafficking. Similar in vitro strategies have been used to elucidate naturally occurring GPCR mutations. Inactive, over-active or constitutively active receptors have been identified by changes in ligand binding, G-protein coupling, receptor desensitization and receptor recycling. Selected examples reviewed include those disorders resulting from mutations in rhodopsin, thyrotropin, luteinizing hormone, vasopressin and angiotensin receptors. By comparison, the recurrent pharmacogenetic variants are more likely to result in an altered predisposition to complex disease in the population. These common variants may affect receptor sequence without intrinsic phenotype change or spontaneous induction of disease and yet result in significant alteration in drug efficacy. These pharmacogenetic phenomena will be reviewed with respect to a limited sampling of GPCR systems including the orexin/hypocretin system, the beta2 adrenergic receptors, the cysteinyl leukotriene receptors and the calcium-sensing receptor. These developments will be discussed with respect to strategies for drug discovery that take into account the potential for the development of drugs targeted at mutated and wild-type proteins.

Drug Resistance↗
PubMed1982

[Surgical treatment of Prinzmetal variant angina. Coronary artery by pass and plexectomy (author's transl)].

Aorto-coronary by pass, widely accepted in the treatment of patients with coronary artery disease is still controversial in the treatment of Prinzmetal variant angina. Recurrence of attacks, occlusion of grafts and post-operative infarction were frequent by described and seem to be related with the persistence of coronary spasm. Authors propose the association of myocardial revascularization and coronary denervation by resection of periaortic plexi. Results of 50 surgical plexectomies associated with coronary by pass appear far better than by pass alone (mortality 4%, myocardial necrosis 4%, persistence of attacks 4%).

Adult↗
PubMed1998

Keloidal dermatofibroma: report of 10 cases of a new variant.

Dermatofibroma is a common cutaneous tumor. Unusual variants of dermatofibroma that exhibit various epidermal changes or different cellular composition have been described. We observed 10 cases of a novel variant of dermatofibroma characterized by keloidal change within the tumor. Formalin-fixed, paraffin-embedded tissues were used for histochemical and immunohistochemical studies. The patients consisted of six women and four men; median age was 34 years (17 to 59 years). All tumors occurred on the extremities, and six were present for at least 2 years. Tenderness was mentioned in four cases. They were described as erythematous or brown papules 1 cm or smaller. Clinical appearance did not deviate from that of ordinary dermatofibromas. Microscopically, the excised tumors showed a superficial circumscribed area of keloidal change under an atrophic epidermis in an otherwise ordinary dermatofibroma. In the keloidlike area, multinucleated giant cells, hemorrhage, hemosiderin deposits, and scattered KiM1P-positive histiocytes, but not factor XIIIa-positive or CD34-positive cells were present among the thick collagen fibers. There were no known recurrences. This variant dermatofibroma should not be overlooked as a simple keloidal scar. The observation of keloidal change in dermatofibromas may support the connotation that trauma is a possible cause of dermatofibroma. The fact that Asian people are more prone to develop keloid may have led us to find this new variant.

Adolescent↗
PubMed2004

Adaptive immunity is the primary force driving selection of equine infectious anemia virus envelope SU variants during acute infection.

Equine infectious anemia virus (EIAV) is a lentivirus that causes persistent infection in horses. The appearance of antigenically distinct viral variants during recurrent viremic episodes is thought to be due to adaptive immune selection pressure. To test this hypothesis, we evaluated envelope SU cloned sequences from five severe combined immunodeficient (SCID) foals infected with EIAV. Within the SU hypervariable V3 region, 8.5% of the clones had amino acid changes, and 6.4% had amino acid changes within the known cytotoxic T lymphocyte (CTL) epitope Env-RW12. Of all the SU clones, only 3.1% had amino acid changes affecting potential N-linked glycosylation sites. In contrast, a much higher degree of variation was evident in SU sequences obtained from four EIAV-infected immunocompetent foals. Within V3, 68.8% of the clones contained amino acid changes, and 50% of the clones had amino acid changes within the Env-RW12 CTL epitope. Notably, 31.9% of the clones had amino acid changes affecting one or more glycosylation sites. Marked amino acid variation occurred in cloned SU sequences from an immune-reconstituted EIAV-infected SCID foal. Of these clones, 100% had amino acid changes within V3, 100% had amino acid changes within Env-RW12, and 97.5% had amino acid changes affecting glycosylation sites. Analysis of synonymous and nonsynonymous nucleotide substitutions revealed statistically significant differences between SCID and immunocompetent foals and between SCID foals and the reconstituted SCID foal. Interestingly, amino acid selection at one site occurred independently of adaptive immune status. Not only do these data indicate that adaptive immunity primarily drives the selection of EIAV SU variants, but also they demonstrate that other selective forces exist during acute infection.

Acute Disease↗
PubMed2022

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Exons↗
PubMed2006

Germline ATBF1 mutations and prostate cancer risk.

BACKGROUND: ATBF1 has been recently identified as a candidate prostate tumor suppressor gene. In addition to more unique mutations, two somatic mutations (shortening of a polypyrimidine tract [Poly(T)n] and a deletion beginning at codon 3381 (3381del)) were each observed in multiple prostate cancer samples and both appear to have an impact on ATBF1 gene function and expression. METHODS: We assayed two recurrent sequence variants in germline DNA from prostate cancer cases and controls, and examined whether carriers of these variants are at increased risk for prostate cancer. RESULTS: We found Poly(T)n variants in both normal and matched tumor DNA samples from multiple patients, indicating a germline origin in each case. Genotyping germline DNA samples indicated that 3381del was significantly associated with prostate cancer risk among sporadic cases (P = 0.03), but not among men with hereditary disease. CONCLUSIONS: Our study indicates that the germline 3381del allele may influence prostate cancer susceptibility.

Alleles↗
PubMed1992

Cellular variant of extraskeletal myxoid chondrosarcoma of abdominal wall--a case report with comparative immunohistochemical study on cartilaginous collagenous proteins in various myxoid mesenchymal tumors.

A rare cellular variant of recurrent extraskeletal myxoid chondrosarcoma occurring in the right lower abdominal wall of a 70-year-old man, is presented with emphasis on a characteristic distribution pattern of cartilaginous collagen proteins in the stroma. While the primary and the first recurrent tumors showed the typical histology of extraskeletal myxoid chondrosarcoma, the later tumor, which recurred 14 years after the first resection, comprised mostly compact nodules of proliferating anaplastic cells with little mucoid stroma. Some areas presented a hemangiopericytomatous pattern. A few nodules possessed abundant myxoid stroma. Immunohistochemically, type II collagen was demonstrated in the stroma of some cellular areas, and type VI collagen was intensely stained around individual tumor cells both in cellular and myxoid areas. In a comparative immunohistochemical study, the same distribution pattern of cartilaginous collagen proteins was observed only in skeletal myxoid chondrosarcomas, but not in other mesenchymal tumors with abundant myxoid stroma. These findings seem to support the cartilaginous nature of extraskeletal myxoid chondrosarcoma, and will facilitate the differential diagnosis of soft-tissue tumors with myxoid stroma.

Abdominal Muscles↗
PubMed1997

[Juvenile Adamantiades-Behçet disease in decreased stimulation with anti-CD3 monoclonal antibody].

A 12 year old boy developed the complete symptom complex of Adamantiades-Behçet's disease over a two-year period. He presented with the mucocutaneous variant with recurrent to persistent oral ulcers which extended into the pharynx, recurrent genital ulcers, perianal lesions, and a positive pathergy test. Ocular involvement and other symptoms associated with the disease were absent. However, the early onset of the disease and the male gender indicated a bad prognosis. The patients father deficiency of suffered from bronchial asthma with recurrent respiratory infections. An IgG-3 subclass was detected. Lymphocyte transformation tests showed markedly diminished response to stimulation with anti-CD3 monoclonal antibody in both patients, while response to PWM, CoA and PHA was normal. In addition, the concentration of serum soluble interleukin 6 receptor was reduced in both patients.

Antibodies, Monoclonal↗
PubMed1999

Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression.

Transcriptional activity of the human serotonin transporter gene (5HTT) is modulated by complex interaction of multiple genomic and cellular factors. Variability of a polymorphic repetitive element (5HTTLPR) is associated with anxiety, depression, and aggression-related traits and may influence the risk to develop affective spectrum disorders. 5HTTLPR variants display a unique DNA secondary structure that has the potential to regulate the transcriptional activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region [del(17)(q11.2)] that is observed in 20-60% of genomic DNA isolated from mononuclear blood cells and postmortem brain. The localization of the deletion breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a V(D)J recombinase-like rearrangement event. In comparison with healthy controls, del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant in recurrent unipolar depression. Our results also suggest that mosaicism of del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR-dependent mechanisms. The findings confirm that the pericentric region of human chromosome 17 is highly unstable and furnishs additional evidence for intricate complexity of 5HTT regulation under physiological condition and in disease.

Adult↗