Compound heterozygosity in sodium channel Nav1.7 in a family with hereditary erythermalgia.

Contains fulltext : 71477.pdf (publisher's version ) (Open Access)Hereditary erythermalgia is a painful and debilitating genetic disorder associated with mutations in voltage-gated sodium channel Nav1.7. We have previously reported a Canadian family segregating erythermalgia consistently with a dominant genetic etiology. Molecular analysis of the proband from the family detected two different missense mutations in Nav1.7. In the present study we have performed a long-term follow-up clinical study of disease progression in three affected family members. A more extensive molecular study has also been completed, analyzing the segregation of the two missense variants in the family. The two variants (P610T, L858F) segregate independently with respect to clinical presentation. Detailed genotype/phenotype correlation suggests that one of the two variants (L858F) is causal for erythermalgia. The second variant (P610T) may modify the phenotype in the proband. This is the second reported study of potential compound heterozygosity for coding polymorphisms in Nav1.7, the first being in a patient with paroxysmal extreme pain disorder

[From gene to disease; primary erythermalgia--a neuropathic disease as a consequence of mutations in a sodium pump gene],Van gen naar ziekte; de neuropathische ziekte 'primaire erythermalgie' als gevolg van mutaties in een natriumpompgen.

Contains fulltext : 51245.pdf (publisher's version ) (Closed access)Primary erythermalgia is a rare autosomal dominant inherited disorder characterized by recurrent attacks of red, warm and painful burning extremities. The gene involved in primary erythermalgia, SCN9A, encodes for a voltage dependent sodium channel alpha subunit (NaV1.7). NaV1.7 is located in dorsal root ganglions and in nociceptive peripheral neurons. It has been hypothesized that mutations lead to a gain of function and hyperexcitability of peripheral sensory neurons contributing to symptoms in primary erythermalgia

[From gene to disease; hepatocystin and autosomal dominant polycystic liver disease]

Polycystic liver disease (PCLD, MIM 174050) is a dominantly inherited condition characterised by the presence in the liver of multiple cysts of biliary epithelial origin. It must be distinguished from autosomal dominant polycystic kidney disease type 1 (ADPKD-1, MIM 173900) and type 2 (ADPKD-2). Both disorders may be complicated by polycystic liver disease, but renal involvement is absent in PCLD. PCLD is often asymptomatic, but if symptoms arise, they are usually due to the mass effect of cysts. The phenotype is more severe in females and correlates with the number of pregnancies or estrogen use. The gene for PCLD has been assigned to chromosome 19p13.2-13.1. Two separate large-scale positional cloning efforts have managed to identify PRKCSH as the gene underlying PCLD. Up to now, all mutations found in PRKCSH introduce stopcodons in the m-RNA, resulting in premature termination of translation to protein. This suggests a loss of function of the encoding protein. The protein, designated by us as hepatocystin, is predicted to be localised in the endoplasmic reticulum. Multiple biological roles have been suggested for hepatocystin, such as a substrate for phosphorylation by protein kinase C, binding to advanced glycation endproducts, and a function as the non-catalytic beta-subunit of glucosidase-II. The role of hepatocystin in PCLD, however, remains to be elucidated

Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert's syndrome.

BACKGROUND/AIMS: UDP-glucuronosyltransferases (UGTs) are important enzymes involved in glucuronidation of various exogenous and endogenous compounds. Studies were undertaken on the variability of three UGT enzyme activities in human livers. Enzyme activities were associated with genetic polymorphisms in UGT1A1 (UGT1A1*28) and UGT1A6 (UGT1A6*2). UGT1A1*28 is associated with Gilbert's syndrome, a deficiency in glucuronidation of bilirubin leading to mild hyperbilirubinemia, whereas UGT1A6*2 may result in low glucuronidation rates of several drugs. METHODS: Enzyme activities and genetic polymorphisms were assessed in 39 human liver samples, and polymorphisms were also assessed in blood of 253 healthy controls. RESULTS: Associations were found between UGT enzyme activities of bilirubin (B) and 4-nitrophenol (NP; r=0.47, P=0.0024), B and 4-methylumbelliferone (MUB; r=0.54, P=0.0003), and NP and MUB (r=0.89, P<0.0001). In addition to the association between B-UGT enzyme activity and UGT1A1*28 (r=0.45, P=0.0034) as reported earlier, an association between B-UGT and UGT1A6*2 (r=0.43, P=0.007) was found. In 253 Dutch Caucasian controls, co-occurrence of UGT1A1*28 and UGT1A6*2 was found (r=0.9, P<0.0001). CONCLUSIONS: Most patients with Gilbert's syndrome, in addition to their reduced B-UGT enzyme activity, may have abnormalities in the glucuronidation of aspirin or coumarin- and dopamine-derivatives, due to this combination of UGT1A1*28 and UGT1A6*2 genotypes

[From gene to disease; primary erythermalgia--a neuropathic disease as a consequence of mutations in a sodium pump gene]

Primary erythermalgia is a rare autosomal dominant inherited disorder characterized by recurrent attacks of red, warm and painful burning extremities. The gene involved in primary erythermalgia, SCN9A, encodes for a voltage dependent sodium channel alpha subunit (NaV1.7). NaV1.7 is located in dorsal root ganglions and in nociceptive peripheral neurons. It has been hypothesized that mutations lead to a gain of function and hyperexcitability of peripheral sensory neurons contributing to symptoms in primary erythermalgia

Over-expression of COX-2 mRNA in colorectal cancer

Contains fulltext : 136453.pdf (publisher's version ) (Open Access)BACKGROUND: Cyclooxygenase-2 (COX-2, PTGS2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of biologic processes such as inflammation, cell proliferation and angiogenesis. COX-2 over-expression was reported in many (pre) malignant tissues, but data strongly vary and seem to depend on the methodology used. METHODS: Normal colorectal mucosa and paired cancerous tissue from 60 patients with colorectal cancer was investigated for the levels of COX-2 mRNA by real-time quantitative Polymerase Chain Reaction (qPCR). COX-2 levels were expressed relative to either: tissue weight or levels of the housekeeping genes beta-2 microglobulin (B2M) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: COX-2 mRNA levels, normalized with respect to tissue weight or mRNA levels of the housekeeping genes B2M or GAPDH, were over-expressed in 80%, 70% and 40% of the colorectal tumor tissues, as compared to the paired adjacent normal colorectal mucosa samples, respectively. Highest mRNA COX-2 ratios tumor/normal were measured when expressed per mg tissue (mean ratio 21.6). When normalized with respect to the housekeeping genes B2M or GAPDH, mean tumor/normal ratios were 16.1 and 7.5, respectively. CONCLUSION: Expression of COX-2 mRNA levels per mg tissue is most simple in comparison to normalization with respect to the housekeeping genes B2M or GAPDH. Levels of COX-2 mRNA are found over-expressed in almost 80% of the colorectal tumors, compared to paired adjacent normal colorectal mucosa, suggesting a role of COX-2 as a potential biomarker for cancer risk, whereas inhibitors of COX-2 could be of value in chemoprevention of colon cancer

Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.

Contains fulltext : 47573.pdf (publisher's version ) (Open Access)Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Recently, mutations in two causative genes for ADPLD, independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way

Duodenal mucosal risk markers in patients with familial adenomatous polyposis: effects of celecoxib/ursodeoxycholic acid co-treatment and comparison with patient controls

Contains fulltext : 125358.pdf (publisher's version ) (Open Access)BACKGROUND: Familial adenomatous polyposis (FAP) is a disease characterized by the development of hundreds to thousands of adenomatous polyps in the colorectum early in life. Virtually all patients with FAP will develop colorectal cancer before the age of 40 to 50 years, unless prophylactic colectomy is performed, which significantly improves their prognosis. The mortality pattern has changed and duodenal cancer now is one of the main cancer-related causes of death in these patients. Practically all patients with FAP develop premalignant duodenal adenomas, which may develop to duodenal cancer in approximately 3-7% of patients. Duodenal cancer in patients with FAP has a poor prognosis. The clinical challenge is to identify patients at high-risk for duodenal carcinoma. Chemoprevention would be desirable to avoid duodenectomy. The main goal of this study is to identify risk markers in normal duodenal mucosa of patients with FAP, that could help identify patients at increased risk for malignant transformation. METHODS: Messenger RNA (mRNA) levels of glutathione S-transferase A1 (GSTA1), glutathione S-transferase P1 (GSTP1), KIAA1199, E-cadherin, peroxisome proliferative activated receptor delta (PPARdelta), caspase-3, cyclin D1, beta-catenin, and cyclooxygenase-2 (COX-2) were measured in duodenal mucosa, using the QuantiGene 2.0 Plex assay. Levels in normal appearing mucosa of patients with FAP (n = 37) were compared with levels in non-FAP patient controls (n = 16). In addition, levels before and after treatment with either celecoxib & ursodeoxycholic acid (UDCA, n = 14) or celecoxib & placebo (n = 13) were evaluated in patients with FAP. RESULTS: mRNA levels of glutathione S-transferase A1 (28.16% vs. 38.24%, p = 0.008) and caspase-3 (3.30% vs. 5.31%, p = 0.001) were significantly lower in patients with FAP vs. non-FAP patient controls, respectively. COX-2 mRNA levels in normal duodenal mucosa of patients with FAP were found to be unexpectedly low. None of the potential risk markers was influenced by celecoxib or celecoxib & UDCA. CONCLUSIONS: Protection against toxins and carcinogens (GSTA1) and apoptosis (caspase-3) is low in patients with FAP, which could contribute to increased susceptibility for malignant transformation of duodenal mucosa. TRIAL REGISTRATION: http://ClinicalTrials.gov number NCT00808743

[Dutch patients with hereditary pancreatitis; high mutation frequency, relatively little pain],[Dutch patients with hereditary pancreatitis; high mutation frequency, relatively little pain]

Contains fulltext : 79789.pdf (publisher's version ) (Closed access)OBJECTIVE: To assess genetic, clinical and morphological characteristics of hereditary pancreatitis, a rare type of chronic pancreatitis with an early onset of symptoms, which is, among others, caused by mutations in the PRSS1 gene. DESIGN: Observational cohort study. METHOD: The study population consisted of 496 patients (27,375 person-years) who were referred to Radboud University Nijmegen Medical Centre for molecular diagnosis of hereditary pancreatitis during period 2000 to 2007. 61 patients with a positive family history of hereditary pancreatitis were selected. Analysis for PRSS1 gene mutations was performed by complete sequence analysis of the exons. All patients received a structured questionnaire. Results : From 25 families 61 patients were included (2,047 person-years). PRSS1 mutations were detected in 52 patients (85.2%): p.R122H (67.2%), p.N29I (14.8%), p.E79K (1.6%), p.N29T (1.6%). In the 40 patients whose clinical data were known the median age at diagnosis was 10.5 years (range: 0-42 years). Pain was reported in 28 (70% of 40 patients in whom all information was complete). 27 patients (67.5%) were admitted to the hospital once or more due to the attacks of pancreatitis. Exocrine and endocrine dysfunction was seen in 6 patients (15%). 24 patients (60%) had undergone a surgical intervention, 10 of whom had undergone a pancreaticojejunostomy. A family history of pancreatic carcinoma was found in 5 patients (12.5%). CONCLUSION: The percentage of PRSS1 mutation was high (85.2%) among this Dutch population that was selected on basis of a positive family history of hereditary pancreatitis. Most patients had no chronic pain