Disturbance in the HIF-1α pathway associated with erythrocytosis: Further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene

Al-Sheikh, Maha; Moradkhani, Kamran; Lopez, Marc; Wajcman, Henri; Préhu, Claude

doi:10.1016/j.bcmd.2007.07.017

Cited by 46 publications

(38 citation statements)

References 25 publications

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“…Recently, a similar phenotype of high erythropoietinassociated polycythemia without associated tumors has been reported in carriers of heterozygous germline mutations in the PHD2 and HIF-2A genes, [12][13][14][15][16][17][18][19] with the exception of one patient carrying a H374R-PHD2 mutation. 20 This particular patient simultaneously developed congenital secondary erythrocytosis and recurrent paraganglioma, a tumor originating from neural crest cells similar to pheochromocytoma but with an extra-adrenal localization.…”

Section: Introductionmentioning

confidence: 53%

“…7 Moreover, PHD2 has been reported to have hydroxylation-independent gene regulatory functions. [35][36][37] Another category, including the PHD2-R398X mutation and three other PHD2 truncated mutations described previously, 12 can be compared to the VHL truncation mutations (VHL disease type 1) which are not associated with the development of pheochromocytomas. Subject with these first two categories could be considered at low risk of developing paraganglioma/pheochromocytoma.…”

Section: Discussionmentioning

confidence: 99%

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Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Ladroue

Hoogewijs²,

Gad³

et al. 2011

Haematologica

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BackgroundCongenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. Design and MethodsFive PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. ResultsThis functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. ConclusionsAs observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.Key words: hypoxia inducible factor, hypoxia-inducible transcription factor, PHD2, erythrocytosis.Citation: Ladroue C, Hoogewijs D, Gad S, Carcenac R, Storti F, Barrois M, Gimenez-Roqueplo A-P, Leporrier M, Casadevall N, Hermine O, Kiladjian J-J, Baruchel A, Fakhoury F, Bressac-de Paillerets B, Feunteun J, Mazure N, Pouysségur J, Wenger RH, Richard S, and Gardie B. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica 2012;97(1):9-14.

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Section: Introductionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Ladroue

Hoogewijs²,

Gad³

et al. 2011

Haematologica

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“…N203K, found in Patient 1, flanks the M202 residue in the helice α1 ( Figure 2B), previously found to be mutated in IE, 18 and introduces a positive charged amino acid with a long side chain in place of a polar asparagine. The patient with this new genetic variation is also affected by a complex mutation in the exon 12 of JAK2.…”

Section: Resultsmentioning

confidence: 80%

“…All the three new erythrocytosis-associated PHD2 mutations here reported involve the catalytic domain of the protein and add to those already known (Figure 2A-B). [16][17][18][19] We previously described as mutation a germ-line missense substitution, 20 Q157H, found in association with JAK2 V617F in a propositus with polycythemia vera and found in an isolated form also in his son, presenting only with mild erythrocytosis. Q157H has been reported also as SNP (NCBI entry, rs61750991) with a frequency of around 2% in normal subjects but with a much higher frequency in cancer patients.…”

Section: Resultsmentioning

confidence: 99%

“…Three additional heterozygous PHD2 mutations have been identified, producing truncated proteins lacking the catalytic domain (M202IfsX71, R281TfsX3) 18 or removing the last C-terminal amino acids tail (Q377X). 18 Finally, the H374R variation has been recently identified in a patient with erythrocytosis and recurrent paraganglioma, 19 suggesting that PHD2 can also act as a tumor-suppressor gene. Our series of newly identified mutations are all germ-line and missense type, coding predicted mutant full length PHD2 proteins of 426 amino acids.…”

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Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene

Albiero¹,

Ruggeri²,

Fortuna³

et al. 2011

Haematologica

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The oxygen sensing pathway modulates erythropoietin expression. In normal cells, intracellular oxygen tensions are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins. PHD2 isozyme has a key role in tagging hypoxia-inducible factor (HIF)-α subunits for polyubiquitination and proteasomal degradation. Erythrocytosis-associated PHD2 mutations reduce hydroxylation of HIF-α. The investigation of 67 patients with isolated erythrocytosis, either sporadic or familial, allowed the identification of three novel mutations in the catalytic domain of the PHD2 protein. All new mutations are germ-line, heterozygous and missense, and code for a predicted full length mutant PHD2 protein. Identification of the disease-causing genes will be of critical importance for a better classification of familial and acquired erythrocytosis, offering additional insight into the erythropoietin regulating oxygen sensing pathway. Sequencing analysisThe PCR products were purified. Sequencing reactions were carried out using Big Dye ® sequencing kit (Applied Biosystems). Direct sequencing was performed in both directions for all samples on an automated sequencer ABI Prism ® 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). Electropherograms were compared with the PHD2 (NCBI GenBank accession n. NM_022051), VHL (NCBI GenBank accession n. NM_000551) and HIF2A (NCBI GenBank accession n. NC_000002) wild-type sequences. Mutations were named in accordance with the standard international nomenclature guidelines recommended by the Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen/). Characterization of the new PHD2 mutationsTo confirm the identity of the newly identified mutations, allele-specific PCR (AS-PCR) was performed for each allelic variant ( Figure 1B). Reaction mixtures were run on a GeneAmp ® PCR System 2700 at standard conditions and PCR fragments were analyzed by agarose gel. Primer sequences and PCR fragment lengths are listed in Online Supplementary Table S1.The germ-line origin of these new genetic lesions was confirmed by their identification on DNA obtained from epithelial cells (buccal cotton-swab sampling) of the probands.DNA samples from peripheral blood mononuclear cells from 100 normal controls with the same ethnic background were also screened for the novel mutations, by means of AS-PCR. Control DNA was obtained from the DNA samples stored in a biobank of healthy subjects at San Bortolo Hospital. Informed consent from the donors to the biobank had already been obtained for research purposes. Results and DiscussionIn this study, three different new germ-line heterozygous mutations of PHD2 were found in a cohort of 67 patients with IE, including 14 and 5 cases subsequently reclassified as PV on the basis of JAK2 V617F or exon 12 mutations. None of the PHD2 mutated subjects was JAK2 V617F positive while one co-harbored JAK2-exon 12 mutation. Main clinical and laboratory features of mutated patients are listed in Table 1.In Patient 1, molecular studies revealed a C>G missense mutati...

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Genetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis

Percy¹,

Rumi²

2008

American J Hematol

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Familial and acquired erythrocytosis and thrombocytosis are characterized by myeloid lineage hyperproliferation, which is either single or multi‐lineage in origin. The single lineage disorders exhibit Mendelian inheritance with polyclonal hematopoiesis and often arise from a single genetic defect. In contrast, the multi‐lineage disorders exhibit complex patterns of inheritance with multi‐genetic origins and clonal hematopoiesis. They have the potential to acquire JAK2 somatic mutations, but this is not the primary event. Identification of the disease‐causing genes will enable better classification of familial and acquired erythrocytosis and thrombocytosis. Furthermore, it will provide an insight into the mechanisms regulating myeloid cell proliferation. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc.

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Disturbance in the HIF-1α pathway associated with erythrocytosis: Further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene

Cited by 46 publications

References 25 publications

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene

Genetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis

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