Hemochromatosis type 4 is one of the most common causes of primary iron overload, after
-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense mutations in
This ...gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous missense mutations in
are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare
variations are fortuitously observed in patients with a secondary cause of hyperferritinemia. Structure/function analysis is the most effective way of establishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We present the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevated serum ferritin concentrations and normal to low transferrin saturation levels.
experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mislocalization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformational changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of-function mutations and that the study of "gating residues" is necessary in order to fully understand the action mechanism of FPN1.
Macrophage migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine sustaining the acute response to gram-negative bacteria and a regulatory role for MIF in Cystic Fibrosis has been suggested ...by the presence of a functional, polymorphic, four-nucleotide repeat in this gene's promoter at position -794, with the 5-repeat allele displaying lower promoter activity. We aimed at assessing the association of this polymorphism with disease severity in a group of Cystic Fibrosis patients homozygous for F508del CFTR gene mutation. Genotype frequencies were determined in 189 Cystic Fibrosis and 134 control subjects; key clinical features of patients were recorded and compared among homozygous 5-allele patients and the other MIF genotypes. Patients homozygous for the 5-repeat allele of MIF promoter displayed a slower rate of lung function decline (p = 0.027) at multivariate survival analysis. Multiple regression analysis on age-normalized respiratory volume showed no association of the homozygous 5-repeat genotype with lung function under stable conditions and no correlation with P.aeruginosa chronic colonization. Therefore, only the Homozygous 5-repeat genotype at MIF -794 is associated with milder disease in F508del Cystic Fibrosis patients.
Summary
Dysregulation of MYC is the genetic hallmark of Burkitt lymphoma (BL) but it is encountered in other aggressive mature B‐cell lymphomas. MYC dysregulation needs other cooperating events for ...BL development. We aimed to characterize these events and assess the differences between adult and paediatric BLs that may explain the different outcomes in these two populations. We analysed patterns of genetic aberrations in a series of 24 BLs: 11 adults and 13 children. We looked for genomic imbalances (copy number variations), copy‐neutral loss of heterozygosity (CN‐LOH) and mutations in TP53, CDKN2A, ID3 (exon 1), TCF3 (exon17) and CCND3 (exon 6). Young patients displayed more frequent 13q31.3q32.1 amplification, 7q32q36 gain and 5q23.3 CN‐LOH, while 17p13 and 18q21.3 CN‐LOH were only detected in adult BLs. ID3 mutations were present in all adult samples, but only in 42% of childhood cases. CCND3 and ID3 double‐hit mutations, as well as 18q21 CN‐LOH, seemed to be associated with poorer outcome. For the first time, we report different genetic anomalies between adult and paediatric BLs, suggesting age‐related heterogeneity in Burkitt lymphomagenesis. This may explain the poorer prognosis of adult BLs. Additional studies are needed to confirm these results in the setting of clinical trials.
The Argentinian population is mainly of Caucasian origin, with a small contingent of indigenous descent. The aim of this study is to test the hypothesis that a panel of mutations designed for ...European countries is not optimal as a first-line molecular diagnosis for routine use in this country of mixed European origin.
Phenotype analyses combined with a European screening panel of 71 mutations followed by Sanger sequencing and large rearrangement study, were used to characterize the identification and distribution of CFTR mutations in the Santa Fe province of Argentina.
Clinical review of 121 subjects suspected of CF during childhood led to selection of 83 unrelated patients. Thirty four different mutations, including two new ones, c.2554dupT and p.Leu49Pro, were detected. The total sensitivity was 91% (n=151/166 alleles).
Frequencies of CFTR mutations in Argentinian populations differ from those of their European ancestry. A new first line panel of 21 CFTR mutations with a sensitivity of 84% is proposed for routine use in central Argentina.
•A European panel of 71 CFTR mutations is not optimal for first-line diagnosis in the mixed population of central Argentina.•Complete screening of the gene lead to a detection rate of 91%.•Two new likely disease-causing mutations were identified.•A new first line panel of 21 CFTR mutations with a sensitivity of 84% is proposed for routine use in central Argentina.
The diagnosis of genetic predisposition in familial pancreatic cancer Boumendjel, Sabrina; Pepermans, Xavier; Antoine-Poirel, Hélène
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
05/2013, Letnik:
13, Številka:
3
Journal Article
Recenzirano
Conclusion: Routine exploration of genes such as BRCA2, PALB2, CDKN2A, listed in order of involvement, is an important initial step towards establishment of a diagnosis of genetic predisposition to ...pancreatic cancer.
Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study ...aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis.
Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68).
Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers.
Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking.
Macrophage migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine sustaining the acute response to gram-negative bacteria and a regulatory role for MIF in Cystic Fibrosis has been suggested ...by the presence of a functional, polymorphic, four-nucleotide repeat in this gene's promoter at position -794, with the 5-repeat allele displaying lower promoter activity. We aimed at assessing the association of this polymorphism with disease severity in a group of Cystic Fibrosis patients homozygous for F508del CFTR gene mutation. Genotype frequencies were determined in 189 Cystic Fibrosis and 134 control subjects; key clinical features of patients were recorded and compared among homozygous 5-allele patients and the other MIF genotypes. Patients homozygous for the 5-repeat allele of MIF promoter displayed a slower rate of lung function decline (p = 0.027) at multivariate survival analysis. Multiple regression analysis on age-normalized respiratory volume showed no association of the homozygous 5-repeat genotype with lung function under stable conditions and no correlation with P.aeruginosa chronic colonization. Therefore, only the Homozygous 5-repeat genotype at MIF -794 is associated with milder disease in F508del Cystic Fibrosis patients.
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