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Results for “mutation co-occurrence”

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PubMed2005

Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity.

Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis. Here we show that among 355 overweight and nonoverweight children, 8.2% were double homozygous for a pair of missense MC3R sequence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: P < 0.0001), had more body fat (body fat mass and percentage fat mass: P < 0.001), and had greater plasma leptin (P < 0.0001) and insulin concentrations (P < 0.001) and greater insulin resistance (P < 0.008) than wild-type or heterozygous children. Both sequence variants were more common in African-American than Caucasian children. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduction, and less protein expression. We conclude that diminished MC3R expression in this double MC3R variant may be a predisposing factor for excessive body weight gain in children.

Adipose Tissue↗
PubMed1999

UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations.

Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified. Mutations in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats, alter bilirubin conjugation. Two missense mutations on one allele of UGT1A6 (UGT1A6*2) result in T181A and R184S amino acid substitutions and reduced activity against phenolics, such as 4-nitrophenol, 4-hydroxycoumarin and butylated hydroxy anisole. We determined the frequency of these polymorphisms in 245 healthy men and women, aged 20-40 years and examined the relationship between TA repeat number and serum bilirubin concentrations in a subset of 24 Asians and 169 Caucasians. The frequencies of the UGT1A1*28 genotypes were 0.537, 0.348, 0.098, 0.008 and 0.008 for promoter TA repeats 6/6, 6/7, 7/7, 5/6 and 6/8, respectively. Both allele and genotype frequencies varied by race (P < 0.02), with 11% of the Caucasians and none of the Asians having the 7/7 genotype. Within both ethnic groups, serum bilirubin increased with increased numbers of UGT1A1 promoter TA repeats (P = 0.0001). However, a strong ethnic group-by-UGT1A1 genotype interaction suggests that additional ethnic differences in bilirubin metabolism contribute to observed bilirubin concentrations. Genotype frequencies for UGT1A6*2 were 0.478, 0.392, 0.029, 0.090, 0.012 for wild-type (wt)/wt, wt/T181A + R184S, wt/R184S, T181A + R184S/T181A + R184S and T181A + R184S/R184S, respectively. The co-occurrence of polymorphisms in UGT1A1 and UGT1A6 differed from that expected (P < 0.0001): individuals homozygous wild-type for UGT1A1 and UGT1A6 were observed at twice the expected frequency; individuals homozygous variant for both genes were ten-fold more frequent and individuals homozygous wild-type for one gene and homozygous variant for the other were ten-fold less frequent than expected. Overall, 8% were homozygous variant for both UGT1 polymorphisms and 43% had at least one variant allele for both UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms, which result in modified expression and activity of UGTs, may influence susceptibility to cancers associated with altered metabolism of endogenous and xenobiotic compounds.

Asian People↗
PubMed2025

Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung cohort reveals new metastasis-associated copy-number alterations including frequent mutant-specific KRAS-allelic imbalance and identifies CDKN2A homozygous deletions as an independent biomarker of poor prognosis.

BACKGROUND: Identifying molecular alterations specific to advanced lung adenocarcinomas could provide insights into tumour progression and dissemination mechanisms. METHOD: We analysed tumour samples, either from locoregional lesions or distant metastases, from patients with advanced lung adenocarcinoma from the SAFIR02-Lung trial by targeted sequencing of 45 cancer genes and comparative genomic hybridisation array and compared them to early tumours samples from The Cancer Genome Atlas. RESULTS: Differences in copy-number alterations frequencies suggest the involvement in tumour progression of LAMB3, TNN/KIAA0040/TNR, KRAS, DAB2, MYC, EPHA3 and VIPR2, and in metastatic dissemination of AREG, ZNF503, PAX8, MMP13, JAM3, and MTURN. Conversely, no meaningful difference was found in pathogenic single-nucleotide variant frequencies, reinforcing the notion that they are early events in tumorigenesis. CDKN2A homozygous deletion was linked to poor clinical outcome in patients with early tumours (overall survival hazard ratio 2.17, 95% CI: 1.43-3.28, corrected p-value&#x2009;=&#x2009;0.01). Furthermore, we found that KRAS mutant allele specific imbalance, i.e. focal amplification of the mutant allele, is more prevalent in locoregional or distant samples of metastatic patients than in early lesions (8.4%, 13% and 2.8% respectively). This observation was replicated in three public cohorts. Tumours with KRAS mutant allele specific imbalance show specific patterns of co-occurrence and mutual exclusion with alterations in key cancer genes like CDKN2A, TP53, STK11 and NKX2-1, often in a tumour type dependent manner. CONCLUSION: Advanced LUAD tumours exhibit higher copy-number alteration burden, with distinct alterations associated with tumour progression and metastasis. CDKN2A homozygous deletions predict poor prognosis in early disease, while KRAS mutant allele-specific imbalance is enriched in advanced tumours.

Humans↗
PubMed2001

Hypothesis. Bystanders or bad seeds? Many autoimmune-target cells may be transforming to cancer and signalling "danger" to the immune system.

Autoimmune-target cells in autoimmune disease (AID) are usually construed as constitutionally normal healthy cells. A related assumption is that other cells in the body of AID patients, except for certain immunocytes, are healthy cells. An implication of that view is that any systemic pathology in organ-specific AID is related to metabolic derangements secondary to tissue destruction. However, much data on target and other cells in AID suggest widespread primary cellular defects. In insulin-dependent diabetes mellitus (IDDM), for example, many "complications" such as atherosclerosis, premature arterial stiffening, senescence of fibroblasts in vitro, and exuberant growth of smooth muscle and mesangial cells in vivo are not strictly attributable to glucose elevation. Also unexplained is the similar appearance of IDDM beta-cells and cells from insulinoma and why the prodromal phase of IDDM has many insulinoma-like features. While AID target cells have often been likened to neoplastic cells, investigators have rarely explored the possibility that autoimmunity in AID is fundamentally antineoplastic. This is likely because the dominant ideas in oncology and immunology-somatic mutation and clonal deletion, respectively-have prevented explanations for how normal immunity could detect transforming cells not expressing non-self antigens. New and less conventional theories of cancer and immunity have facilitated such an explanation. I use Rubin's "epigenetic" aging model of carcinogenesis and Matzinger's "danger" model of immunity to integrate the immunological and oncological sides of AID. In particular, I postulate that individuals suffering from AID have inherited many foci of prematurely aging cells. Those inherently damaged cells adapt to in vivo challenges by beginning to transform into cancer cells. However, as long as those stressed cells have not fully transformed, they will continue to signal "danger" to the innate immune system. The clinical outcome of that struggle between incipient neoplasia and immunity will vary depending upon the degree of tumor-proneness and resistance of the individual. Borrowing from cancer geneticist Henry Lynch, I postulate that tumor-resistance is inherited as a quantitative polygenic trait in direct proportion to tumor-proneness. I further contend that tumor-proneness and immunity are linked polygenic traits such that the greater one's tumor-proneness, the more powerful his/her antitumor immunity. I point to the shared DNA repair deficiency of certain cancer-prone syndromes and HLA-linked AID, their occasional co-occurrence, and their demonstrably exceptional immunity against solid tumors. I propose that HLA-linked AID constitute "chronic hypersensitivity syndromes" due to immunity's largely hidden battle to suppress multiple incipient neoplastic microfoci. Much of the physiopathology of AID is explicable as a sustained systemic response to threatened neoplastic transformation.

Animals↗
PubMed2000

Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred.

Several reports exist of the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and Marfan syndrome, including a report of ADPKD and "overlap" connective tissue disorder in a family with linkage to the PKD1 locus. We report the results of clinical and linkage investigations of an ADPKD family in whom several affected subjects also had aortic vascular complications as well as features of Marfan syndrome. Detailed clinical assessment and linkage analysis were performed with polymorphic microsatellite markers closely linked to the PKD1 and FBN1 loci. Survival data were compared with 10 geographically matched PKD1 families. Although several subjects had features of both ADPKD and Marfan syndrome, detailed clinical examination of the extended family indicated that the two conditions had converged within the kindred. For those with ADPKD, linkage was established to the PKD1 locus (lod score, 6.04). Among those with features of Marfan syndrome, linkage was confirmed to the FBN1 locus (lod score, 1.87). Five of six subjects with both ADPKD and the high-risk FBN1 haplotype had associated vascular complications. In contrast, among the remaining nine individuals with PKD1 alone, seven had aortic assessments, and none were found to have aortic complications. Our experience suggests that when prominent features of connective tissue disease or vascular complications are found in ADPKD patients, alternative additional diagnoses should be considered, including the possibility of a coinherited FBN1 mutation responsible for Marfan syndrome or, alternatively, an associated milder FBN1 phenotype in the absence of sufficient other clinical features to allow Marfan syndrome to be diagnosed.

Adult↗
PubMed2005

Family-based and case-control association studies of glutamate receptor GRIK3 Ser310Ala polymorphism in Polish patients and families with alcohol dependence.

The aim of this study was to evaluate the role of the GRIK3 functional polymorphism (Ser310Ala) in the pathogenesis of alcoholism. This polymorphism was investigated in two types of studies: (1) the association study in a whole group of alcoholics (116 patients fulfilling ICD-10 alcohol dependence (AD) criteria and 255 controls, Polish descent) and homogenous overlapping subgroups of patients with: a history of delirium tremens and/or alcohol seizures, early age of onset of alcoholism (AOO<26 years), a co-occurrence of dissocial personality disorder, a history of familial alcoholism; (2) the family-based study (using Transmission Disequilibrium Test (TDT) in 100 Polish families with alcohol dependence). The history of alcoholism was obtained using SSAGA (Polish version). GRIK3 functional polymorphism was determined using PCR. TDT revealed an adequate transmission of both alleles to the affected offspring in the whole group of alcohol families (29 x Ser, 24 x Ala; chi2=0.472; d.f.=1; p=0.492) and in the homogenous subgroups of families. No significant associations between any of the above mentioned alcohol phenotypes and Ser310 allele were observed (the whole AD group: p=0.66 AD with delirium and/or seizures: p=0.521; early onset AD: p=0.868; AD with familial history of alcoholism: p=0.798 and AD with dissocial personality disorder: p=0.618). These findings do not seem to support the hypothesis of the role of this polymorphism in the pathogenesis of alcoholism.

Adult↗
PubMed2006

Oculopharyngeal somatic myopathy in a patient with a novel large-scale 3,399 bp deletion and a homoplasmic T5814C transition of the mitochondrial DNA.

We report a 65-year-old woman with a sporadic form of progressive oculopharyngeal somatic myopathy due to a novel large-scale 3,399 base pair (bp) deletion of the mitochondrial DNA (mtDNA) and co-occurrence of a homoplasmic T5814C transition. The onset of myopathy began from chronic progressive external ophthalmoplegia (CPEO) at age of 20 years. Bulbar weakness, neck and proximal limb paralysis, slowly progressed to eventual respiratory failure. The plasma levels of pyruvate (1.5 mg/dL) and lactate (20.2 mg/dL) were elevated. Muscle biopsy showed decreased enzymatic activity of cytochrome c oxidase, but no ragged-red fibers. Electron microscopy showed "parking-lot" paracrystalline inclusions in the enlarged mitochondria suggestive for mitochondrial myopathy. Sequencing of the whole mitochondrial genome of the patient's muscle and leukocytes showed 3,399 bp deletion of the mtDNA from nucleotide position 8,024 to 11,423 and a homoplasmic thymidine to cytosine transition at nucleotide position 5,814 of the tRNA(Cys) gene of mtDNA (T5814C). T5814C was absent in the white blood cells of the patient's daughter and in 205 normal controls. We conclude that a large-scale deletion may coexist with T5814C transition in patients with sporadic form of mitochondrial cytopathy manifested by slowly progressive oculopharyngeal somatic myopathy.

Aged↗
PubMed2003

Co-occurrence of essential tremor and Parkinson's disease: clinical study of a large kindred with autopsy findings.

A multigenerational family complex with an admixture of essential tremor (ET) and PD is presented. Medical information obtained either by historic documentation and/or examination was available for five generations and included 36 members. Of these, 11 family members had tremor of the limbs and/or head. In all these instances ET made its first appearance at an early age, usually prior to the second decade of life. In one case focal dystonia of the hand, a possible prelude to PD occurred, while in three brothers of the third generation, two of them identical twins, classical Parkinson's disease (PD) developed. They had ET develop at an early age, which persisted and in their 50s began showing evidence of PD. Two decades later the twin brothers succumbed to cancer of the colon and at autopsy typical findings of PD with cell loss in the substantia nigra and Lewy-body formation positive for alpha-synuclein by immunohistochemistry was found. Additionally, more than the usual number of senile plaques and neurofibrillatory tangles were present without clinical evidence of dementia or significant decline in cognitive function. This unusual set of clinical and pathological circumstances can hardly be attributed to chance occurrence and raise the question of a specific genetic mutation and/or clustering, which may link ET with PD.

Adult↗