Abstract Background Tyrosinase ( TYR ) is a key pigmentation gene that is highly polymorphic and responsible for the most common form of autosomal recessive albinism, OCA1. Objective To assess the ...role of frequent and rare TYR variants in predisposition to skin cancer (SK) in the French population. Methods We genotyped a frequent TYR variant (p.R402Q) in 1273 patients {1047 cutaneous melanoma (CM) and 226 basal cell carcinoma (BCC)} and 925 controls, and the full coding region of TYR was sequenced in 287 patients suspected of genetic predisposition to SK (familial and/or multiple SK and/or onset before 40 years) and 187 controls. Results The homozygous p.R402Q variant was significantly associated with SK risk ( P value = 0.008; OR = 1.57), and was mostly associated with multiple CM risk ( P value = 0.021; OR = 2.50) and familial CM risk ( P value = 0.022; OR = 2.16). In addition, 19 rare TYR variants, mainly albinism mutations, were identified in 15 patients and 8 controls. Among these, 3 clearly deleterious mutations (1 non-sense and 2 affecting mRNA splicing) were identified in 3 patients, one of which was homozygous. Conclusion Our data confirmed the association of TYR p.R402Q with SK risk in the French population, and support that rare deleterious TYR variants may also play a role in multi-factorial genetic predisposition to SK. These results should be confirmed by replications studies.
Mutations identified in the fibrillin-1 (FBN1) gene have been associated with Marfan syndrome (MFS). Molecular analysis of the gene is classically performed in probands with MFS to offer diagnosis ...for at-risk relatives and in children highly suspected of MFS. However, FBN1 gene mutations are found in an ill-defined group of diseases termed 'type I fibrillinopathies', which are associated with an increased risk of aortic dilatation and dissection. Thus, there is growing awareness of the need to identify these non-MFS probands, for which FBN1 gene screening should be performed. To answer this need we compiled the molecular data obtained from the screening of the FBN1 gene in 586 probands, which had been addressed to our laboratory for molecular diagnosis. In this group, the efficacy of FBN1 gene screening was high in classical MFS probands (72.5%,), low (58%) in those referred for incomplete MFS and only slight (14.3%) for patients referred as possible MFS. Using recursive partitioning, we found that the best predictor of the identification of a mutation in the FBN1 gene was the presence of features in at least three organ systems, combining one major, and various minor criteria. We also show that our original recommendation of two systems involved with at least one with major criterion represents the minimal criteria because in probands not meeting these criteria, the yield of mutation identification drastically falls. This recommendation should help clinicians and biologists in identifying probands with a high probability of carrying a FBN1 gene mutation, and thus optimize biological resources.
Heterozygotes for the p.Cys282Tyr (C282Y) mutation of the HFE gene do not usually express a hemochromatosis phenotype. Apart from the compound heterozygous state for C282Y and the widespread ...p.His63Asp (H63D) variant allele, other rare HFE mutations can be found in trans on chromosome 6.
We performed molecular investigation of the genes implicated in hereditary hemochromatosis in six patients who presented with iron overload but were simple heterozygotes for the HFE C282Y mutation at first genetic testing. Functional impairment of new variants was deduced from computational methods including molecular modeling studies.
We identified four rare HFE mutant alleles, three of which have not been previously described. One mutation is a 13-nucleotide deletion in exon 6 (c.1022_1034del13, p.His341_Ala345 > LeufsX119), which is predicted to lead to an elongated and unstable protein. The second one is a substitution of the last nucleotide of exon 2 (c.340G > A, p.Glu114Lys) which modifies the relative solvent accessibility in a loop interface. The third mutation, p.Arg67Cys, also lies in exon 2 and introduces a destabilization of the secondary structure within a loop of the α1 domain. We also found the previously reported c.548T > C (p.Leu183Pro) missense mutation in exon 3. No other known iron genes were mutated. We present an algorithm at the clinical and genetic levels for identifying patients deserving further investigation. Conclusions Our results suggest that additional mutations in HFE may have a clinical impact in C282Y carriers. In conjunction with results from previously described cases we conclude that an elevated transferrin saturation level and elevated hepatic iron index should indicate the utility of searching for further HFE mutations in C282Y heterozygotes prior to other iron gene studies.
1 AP-HP, Service de Génétique et Biochimie hormonale, Hôpital Bichat Claude Bernard, Paris, France, Université Paris Diderot, Paris;
2 Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, ...Rennes;
3 INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, Université Paris Diderot, Paris;
4 Service de Médecine Interne, Centre Hospitalier Jacques Cœur, Bourges and
5 Service des Maladies du Foie et Centre de Référence des Surcharges Génétiques en Fer, Hôpital Pontchaillou, Rennes, France
Correspondence: Carole Beaumont, INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris Diderot, site Bichat BP416, 16 Rue Henri Huchard, 75870 Paris cedex 18, France., E-mail: carole.beaumont{at}inserm.fr
Background: Elevated serum ferritin levels are frequently encountered in clinical situations and once iron overload or inflammation has been ruled out, many cases remain unexplained. Genetic causes of hyperferritinemia associated to early cataract include mutations in the iron responsive element in the 5 untranslated region of the L ferritin mRNA, responsible for the hereditary hyperferritinemia cataract syndrome.
Design and Methods: We studied 91 probands with hyperferritinemia comprising 25 family cases belonging to families with at least two cases of unexplained hyperferritinemia, and 66 isolated cases. In the families, we also analyzed 30 relatives. Hyperferritinemia was considered as unexplained when transferrin saturation was below 45% and/or serum iron below 25 µmol/L and/or no tissue iron excess was detected, when inflammation had been ruled out and when iron responsive element mutation was absent. We carried out sequencing analysis of the FTL gene coding the L ferritin.
Results: A novel heterozygous p.Thr30Ile mutation in the NH2 terminus of L ferritin subunit was identified in 17 probands out of the cohort. The mutation was shown to cosegregate with hyperferritinemia in all the 10 families studied. No obvious clinical symptom was found associated with the presence of the mutation. This unique mutation is associated with an unusually high percentage of ferritin glycosylation.
Conclusions: This missense mutation of FTL represents a new cause of genetic hyperferritinemia without iron overload. We hypothesized that the mutation increases the efficacy of L ferritin secretion by increasing the hydrophobicity of the N terminal "A" helix.
Key words: hyperferritinemia, glycosylated ferritin, L ferritin, iron overload.
Related Article
Towards explaining "unexplained hyperferritinemia"
Clara Camaschella, Erika Poggiali
Haematologica 2009 94: 307-309.
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Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by a partial deficiency of ferrochelatase (FECH, EC 4.99.1.1). EPP is transmitted as an autosomal dominant ...disorder with an incomplete penetrance. Using haplotype segregation analysis, we have identified an intronic single nucleotide polymorphism (SNP), IVS3-48T/C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism (NMD), producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression.
Objective
Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is defined as an increase in length and diameter of intracranial arteries. Abdominal aortic ...aneurysm and ectasia of coronary arteries have been reported in association with IADE. In both conditions, a dysfunction of matrix metalloproteinases (MMP)‐2, ‐3, and ‐9 have been found. Our aim was to investigate these MMP pathways in stroke patients with IADE.
Methods
Five hundred ten Caucasians patients with brain infarction were consecutively recruited at 12 centers. The diagnosis of IADE was made by consensus between 2 neurologists based on magnetic resonance imaging scans. Determination of MMP‐2, ‐3, and ‐9 plasma levels was centralized in 1 laboratory. Because we found a threshold effect of MMP‐3 plasma levels with the risk of IADE, determination of the MMP‐3 5A/6A polymorphism was carried out.
Results
IADE was identified in 12% of stroke patients. There was no association of IADE with mean MMP‐2, ‐3, and ‐9 plasma levels. After categorization of MMP plasma levels into tertiles, we found a higher risk of IADE with the lowest MMP‐3 tertile (adjusted odds ratio OR, 2.48; 95% confidence interval CI, 1.17–5.23). In genotype analysis, there was a significant additive effect of the 5A allele on the risk of IADE, with an adjusted OR of 1.62 (95% CI, 1.03–2.55).
Interpretation
In this cohort of stroke patients of Caucasian ancestry, IADE was associated with low MMP‐3 plasma levels and with the 5A/6A polymorphism of the promoter region of MMP‐3. These results suggest that MMP‐3 may play a role in IADE. ANN NEUROL 2010;67:508–515
Ferritin molecules play an important role in the control of intracellular iron distribution and in the constitution of long term iron stores. In vitro studies on recombinant ferritin subunits have ...shown that the ferroxidase activity associated with the H subunit is necessary for iron uptake by the ferritin molecule, whereas the L subunit facilitates iron core formation inside the protein shell. However, plant and bacterial ferritins have only a single type of subunit which probably fulfills both functions. To assess the biological significance of the ferroxidase activity associated with the H subunit, we disrupted the H ferritin gene (Fth) in mice by homologous recombination.Fth+/− mice are healthy, fertile, and do not differ significantly from their control littermates. However,Fth−/− embryos die between 3.5 and 9.5 days of development, suggesting that there is no functional redundancy between the two ferritin subunits and that, in the absence of H subunits, L ferritin homopolymers are not able to maintain iron in a bioavailable and nontoxic form. The pattern of expression of the wild type Fth gene in 9.5-day embryos is suggestive of an important function of the H ferritin gene in the heart.
We report the first case of granulomatous mastitis due to Corynebacterium kroppenstedtii linked to strongly impaired neutrophil responses to Nod2 agonist and a single nucleotide polymorphism within ...the NOD2 gene (SNP13 Leu1007fsinsC) in a heterozygous state. These findings provided the first demonstration of impaired Nod2 function associated with corynebacterial infection.
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