A French CDK4-positive melanoma family with a co-inherited EDNRB mutation.
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Cyclin-Dependent Kinase 4↗
Biomedical subjects
Bernard Grandchamp
Publications and source records attributed to Bernard Grandchamp.
Melanoma susceptibility and progression: Association study between polymorphisms of the chemokine (CCL2) and chemokine receptors (CX3CR1, CCR5).
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Adolescent↗
Severe X-linked chronic granulomatous disease in two unrelated females.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations of one of the subunits of phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to decreased or complete absence of neutrophil oxidative burst. We report the clinical and laboratory findings in two young unrelated females 14 and 9 years of age and natives of Tahiti and Reunion Islands, respectively, with severe X-linked granulomatous disease. In both cases, the infectious pattern was unusual, with convergent symptoms suggesting underlying mycobacterial infection. Functional analysis revealed low residual NADPH oxidase activity with about 5-10% of normal neutrophil population. De novo null mutations affecting the CYBB gene that encodes the gp91 protein were found in both cases in the heterozygous state (in patient 1, p.Arg130X in exon 5, and in patient 2, a novel insertion in exon 6, c.632_633insCATC). Methylation analysis confirmed that phenotype expression was linked to skewed X inactivation and showed that the de novo mutation arose on the maternally inherited chromosome in one case and on the paternally inherited chromosome in the other case. In conclusion, X-linked CGD carriers could therefore be at risk for severe infectious diseases depending on the skewed X inactivation pattern and the infectious context.
Adolescent↗
MC1R and PTCH gene polymorphism in French patients with basal cell carcinomas.
In this study, we assessed the role of melanocortin 1 receptor (MC1R) variants and of two patched (PTCH) polymorphisms (c.3944C>T (P1315L), insertion 18 bp IVS1-83) as risk factors for basal cell carcinoma (BCC) in the French population. The population investigated comprised 126 BCC patients who were enrolled on the basis of specific criteria (multiple and/or familial BCC and/or onset before the age of 40 years and/or association with another tumor)--and 151 controls matched for ethnicity, age, and sex. MC1R variants appeared as a moderate risk factor for BCC (odds ratio (OR) for one and two variants, 2.17 [1.28-3.68] and 7.72 [3.42-17.38], respectively), independently of pigmentation characteristics (OR = 2.53 [1.34-4.8]). Interestingly, in addition to the predictable red hair color (RHC) alleles, two non-RHC alleles (V60L and V92M) were also closely associated with BCC risk (OR 3.21 [1.91-5.38] and 2.87 [1.5-5.48], respectively), which differs from the situation in the Celtic population. In addition, the PTCH c.3944C/C genotype was also associated with BCC risk (OR 1.94 [1.2-3.1]), especially in the subgroup of patients with multiple tumors (OR 2.16 [1.3-3.6]). Thus, our data show that MC1R and PTCH variants are associated with BCC risk in the French population. We further suggest that assessing MC1R and PTCH status could be useful, combined with the assessment of clinical risk factors, in identifying high-risk patients to be targeted for prevention or more rigorous surveillance.
Adult↗
The A148T variant of the CDKN2A gene is not associated with melanoma risk in the French and Italian populations.
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Age Factors↗
Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload.
DMT1 mediates the pH-dependent uptake of Fe(2+) from the diet in duodenal enterocytes and in most other cells. It transfers iron from the endosomes to the cytosol following the uptake of the transferrin-transferrin receptor complex. DMT1 mutations are responsible for severe hypochromic microcytic anemia in rodents and in 2 human patients described recently. We report a compound heterozygote for 2 new DMT1 mutations, associated with microcytic anemia from birth and progressive liver iron overload. The first mutation is a GTG deletion in exon 5, leading to the V114 in-frame deletion in transmembrane domain 2, and the second is a G --> T substitution in exon 8 leading to the G212V replacement in transmembrane domain 5. Together with the 2 previously reported cases, this patient defines a new syndrome of congenital microcytic hypochromic anemia, poorly responsive to oral iron treatment, with liver iron overload associated paradoxically with normal to moderately elevated serum ferritin levels.
Amino Acid Sequence↗
Ferritin and transferrin are both predictive of the onset of hyperglycemia in men and women over 3 years: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study.
OBJECTIVE: The aim of the present work was to determine, in a cohort of men and women, whether ferritin and transferrin were associated with glucose metabolism and whether they were predictive of the onset of hyperglycemia (impaired fasting glycemia or type 2 diabetes) after 3 years of follow-up. RESEARCH DESIGN AND METHODS: Among 4,501 subjects from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, 1,277 subjects (644 men and 633 women) were randomly selected for the analysis of iron biomarkers at baseline and at 3 years. In addition, to determine whether these parameters were relevant to pathological changes, all 231 subjects normoglycemic at baseline and hyperglycemic 3 years later were analyzed for iron biomarkers. RESULTS: At baseline, plasma ferritin concentrations were positively correlated with fasting insulin and fasting glucose in the 1,277 subjects. Although transferrin and ferritin were negatively correlated, transferrin was also positively correlated with fasting insulinemia. Baseline ferritin concentration was an independent predictor of an increase in insulin concentration over a 3-year period (P = 0.002). Further, baseline ferritin and transferrin were independently associated with the onset of hyperglycemia over a 3-year period in the whole population (P < 0.001 for both) and in each sex. CONCLUSIONS: Although negatively correlated, both transferrin and ferritin were positively associated with the onset of abnormalities in glucose metabolism in a prospective study. These results further support the hypothesis of a causative role of iron metabolism in the onset of insulin resistance and type 2 diabetes.
Adult↗
Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from a partial deficiency of ferrochelatase (FECH). Recently, we have shown that the inheritance of the common hypomorphic IVS3-48C allele trans to a deleterious mutation reduces FECH activity to below a critical threshold and accounts for the photosensitivity seen in patients. Rare cases of autosomal recessive inheritance have been reported. We studied a cohort of 173 white French EPP families and a group of 360 unrelated healthy subjects from four ethnic groups. The prevalences of the recessive and dominant autosomal forms of EPP are 4% (95% confidence interval 1-8) and 95% (95% confidence interval 91-99), respectively. In 97.9% of dominant cases, an IVS3-48C allele is co-inherited with the deleterious mutation. The frequency of the IVS3-48C allele differs widely in the Japanese (43%), southeast Asian (31%), white French (11%), North African (2.7%), and black West African (<1%) populations. These differences can be related to the prevalence of EPP in these populations and could account for the absence of EPP in black subjects. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event. Estimation of the age of the IVS3-48C allele from haplotype data in white and Asian populations yields an estimated age three to four times younger in the Japanese than in the white population, and this difference may be attributable either to differing demographic histories or to positive selection for the IVS3-48C allele in the Asian population. Finally, by calculating the KA/KS ratio in humans and chimpanzees, we show that the FECH protein sequence is subject to strong negative pressure. Overall, EPP looks like a Mendelian disorder, in which the prevalence of overt disease depends mainly on the frequency of a single common single-nucleotide polymorphism resulting from a unique mutational event that occurred 60,000 years ago.
Base Sequence↗
A physiological model to study iron recycling in macrophages.
Following erythrophagocytosis (EP) of senescent red blood cells (RBCs), heme iron is recycled to the plasma by tissue macrophages. This process is critical for mammalian iron homeostasis but remains elusive. We characterized a cellular model using artificially-aged murine RBCs and murine bone marrow-derived macrophages (BMDMs) and study mRNA and protein expression of HO-1, ferroportin and ferritin after EP. In vitro ageing of RBCs was obtained by raising intracellular calcium concentration. These RBCs exhibit several features of erythrocyte senescence including externalization of phosphatidyl-serine, specific binding and phagocytosis by BMDMs. During the first hours of EP, we observed a rapid increase of HO-1 and ferroportin mRNAs and proteins, whereas ferritin protein expression was progressively induced with no major changes in RNA levels. At later stages after EP, a different pattern of expression was observed with a net decrease of ferroportin, a sustained high level of HO-1, and a strong increase in ferritins. Taken together, these results suggest that after EP, iron is rapidly extracted from heme and exported by ferroportin. Surprisingly, the gene expression profile at late stages after EP, which is indicative of iron storage, is reminiscent of what is observed in inflammation. However, phagocytosis of artificially-aged red blood cells seems to repress the proinflammatory response of macrophages.
Animals↗
Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria.
Hereditary coproporphyria (HCP), an autosomal dominant acute hepatic porphyria, results from mutations in the gene that encodes coproporphyrinogen III oxidase (CPO). HCP (heterozygous or rarely homozygous) patients present with an acute neurovisceral crisis, sometimes associated with skin lesions. Four patients (two families) have been reported with a clinically distinct variant form of HCP. In such patients, the presence of a specific mutation (K404E) on both alleles or associated with a null allele, produces a unifying syndrome in which hematological disorders predominate: 'harderoporphyria'. Here, we report the fifth case (from a third family) with harderoporphyria. In addition, we show that harderoporphyric patients exhibit iron overload secondary to dyserythropoiesis. To investigate the molecular basis of this peculiar phenotype, we first studied the secondary structure of the human CPO by a predictive method, the hydrophobic cluster analysis (HCA) which allowed us to focus on a region of the enzyme. We then expressed mutant enzymes for each amino acid of the region of interest, as well as all missense mutations reported so far in HCP patients and evaluated the amount of harderoporphyrin in each mutant. Our results strongly suggest that only a few missense mutations, restricted to five amino acids encoded by exon 6, may accumulate significant amounts of harderoporphyrin: D400-K404. Moreover, all other type of mutations or missense mutations mapped elsewhere throughout the CPO gene, lead to coproporphyrin accumulation and subsequently typical HCP. Our findings, reinforced by recent crystallographic results of yeast CPO, shed new light on the genetic predisposition to HCP. It represents a first monogenic metabolic disorder where clinical expression of overt disease is dependent upon the location and type of mutation, resulting either in acute hepatic or in erythropoietic porphyria.
Amino Acid Sequence↗
Association between endothelin receptor B nonsynonymous variants and melanoma risk.
The endothelin signaling pathway plays a crucial role in melanocyte differentiation and migration. In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM). The coding region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 patients (11%), but only two were found in four control subjects (3%, odds ratio [OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which had previously been shown to lead to loss of function. In multivariable logistic regression analysis including skin type, eye and hair color, number of nevi, and dorsal lentigines (freckles), the association between EDNRB mutations and MM risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = .03). Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.
Adult↗
Association of the -92C/G and 807C/T polymorphisms of the alpha2 subunit gene with human platelets alpha2beta1 receptor density.
OBJECTIVE: Platelet adhesion to the subendothelial tissue via the collagen receptor alpha2beta1 is a crucial event in vascular biology. Although evidence has been provided that the number of platelets alpha2beta1 copies is genetically determined, the molecular change primary responsible has not been yet elucidated. The aim of our present study was to investigate the effect of combined polymorphisms within both regulatory (-52C/T and -92C/G) and coding regions (807C/T and 1648A/G) of the alpha2 subunit gene on human platelets alpha2beta1 receptor density and/or susceptibility to coronary artery disease (CAD). METHODS AND RESULTS: Among 254 cardiac surgery patients, no evidence was found for an association between the alpha2 subunit gene polymorphisms and CAD. In contrast, in a subgroup of 113 patients, we observed a significant association between all polymorphisms except -52C/T and alpha2beta1 receptor level. Furthermore, when 3 groups of patients were defined according to the tertiles of platelets alpha2beta1 copies, the -92C/807T haplotype was more frequent in the group of patients with high alpha2beta1 receptor level. CONCLUSIONS: These results suggest that an individual effect of each polymorphism located either in the coding or promoter sequence of the alpha2 gene may act in combination to modulate variations in platelets alpha2beta1 receptor density.
Blood Platelets↗
Effects of intravenous polymaltose iron on oxidant stress and non-transferrin-bound iron in hemodialysis patients.
BACKGROUND: The use of intravenous iron to correct anemia in end-stage renal diseases (ESRD) has been suspected of catalyzing the production of activated oxygen species and promoting oxidative damage. We investigated the pro-oxidative potential of injected iron in hemodialysis patients. METHODS: In study A, 65 patients with ESRD were studied. 20 patients received weekly infusions of iron polymaltose (maltofer), whereas 45 patients had been off iron therapy for more than 2 months. In study B, 12 patients were investigated during two consecutive hemodialysis sessions, one session without and one session with infusion of 100 mg of maltofer over 4 h. Serum iron status, non-transferrin-bound iron (NTBI) and markers of oxidative stress were studied in blood samples from these patients. RESULTS: In study A, NTBI was detected in 41% of the patients and the proportion of NTBI-positive patients was the same whether or not they received iron therapy. In study B, the serum iron and transferrin saturation index increased during iron infusion and NTBI transiently appeared in some patients but markers of oxidative stress were not significantly affected. CONCLUSION: Although ESRD patients have a high prevalence of NTBI in their serum, no correlation could be established between the presence of NTBI and an increased oxidative stress. The slow infusion of maltofer does not promote a significant increase in the plasma concentration of oxidative stress markers. It may therefore be considered as a safe complement to erythropoietin therapy.
Adult↗
Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma.
The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.
Adult↗
Sensitive allele-specific PCR assay able to detect FGFR3 mutations in tumors and urine from patients with urothelial cell carcinoma of the bladder.
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Alleles↗
Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos.
We have previously shown that hepcidin transgenic embryos are severely anemic and die around birth. Here, we report that embryonic hepcidin transgene expression decreases transferrin receptor 1 (TfR1) mRNA level in placenta, as shown by cDNA microarray analysis and quantitative RT-PCR, by a mechanism which is independent of placenta iron content and iron responsive element/iron regulatory protein (IRE/IRP) activity. On the contrary, iron injections into pregnant mothers result in increased placenta iron and ferritin content, and reduced IRE binding activity of IRP1 leading to decreased TfR1 mRNA level. Taken together, these results suggest that hepcidin action on placenta is mostly through transcriptional downregulation of the iron uptake machinery.
Animals↗
Construction of a global score quantifying allelic imbalance among biallelic SIDP markers in bladder cancer.
The purpose of this paper is the construction of an adapted statistical test for urinary detection of bladder cancer based on the assessment of allelic imbalance using biallelic Short Insertion/Deletion Polymorphism DNA markers. This test is based on the comparison of several of these markers, analysed from urinary DNA, to the distribution of their analogues in blood, which is taken as reference. A reproductibility study is first performed in blood in order to make a selection among the 23 available markers and 18 are retained. A global score based on the chi2 distribution is then built to test for allelic imbalance among all informative markers for each patient. It avoids the count of DNA abnormalities marker by marker and allows to take into account the degree of abnormality of each marker. That method is preliminarily evaluated on a sample of 53 patients and 27 controls. The estimated specificity (96.3%) on that reduced sample is satisfactory, whereas sensitivity (60.4%) could be improved by an augmentation of the number of tested markers. Several issues regarding the validity of the method are discussed.
Allelic Imbalance↗
Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias.
We have recently demonstrated that in an autosomal dominant porphyria, erythropoietic protoporphyria (EPP), the coinheritance of a ferrochelatase (FECH) gene defect and of a wild-type low-expressed FECH allele is generally involved in the clinical expression of EPP. This mechanism may provide a model for phenotype modulation by minor variations in the expression of the wild-type allele in the other three autosomal dominant porphyrias that exhibit incomplete penetrance: acute intermittent porphyria (AIP), variegata porphyria (VP) and hereditary coproporphyria (HC), which are caused by partial deficiencies of hydroxy-methyl bilane synthase (HMBS), protoporphyrinogen oxidase (PPOX) and coproporphyrinogen oxidase (CPO), respectively. Given the dominant mode of inheritance of EPP, VP, AIP and HC, we first confirmed that the 200 overtly porphyric subjects (55 EPP, 58 AIP, 56 VP; 31 HC) presented a single mutation restricted to one allele (20 novel mutations and 162 known mutations). We then analysed the available single-nucleotide polymorphisms (SNPs) present at high frequencies in the general population and spreading throughout the FECH, HMBS, PPOX and the CPO genes in four case-control association studies. Finally, we explored the functional consequences of polymorphisms on the abundance of wild-type RNA, and used relative allelic mRNA determinations to find out whether low-expressed HMBS, PPOX and the CPO alleles occur in the general population. We confirm that the wild-type low-expressed allele phenomenon is usually operative in the mechanism of variable penetrance in EPP, but conclude that this is not the case in AIP and VP. For HC, the CPO mRNA determinations strongly suggest that normal CPO alleles with low-expression are present, but whether this low-expression of the wild-type allele could modulate the penetrance of a CPO gene defect in HC families remains to be ascertained.
Acute Disease↗