Congenital erythrocytosis – discover of a new mutation in the EGLN1 gene

Barradas, João; Rodrigues, Catarina Dantas; Ferreira, Gisela; Rocha, Paula Sousa da Silva; Constanço, Conceição; Andrade, Maria Reis; Bento, Celeste; Vitória, Helena

doi:10.1002/ccr3.1499

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…Mutations in the EGLN1 gene are distributed throughout the protein with no hotspot, and no more than two families, of small size, per mutation have been described. 31 In addition, mutations in hypoxia pathway genes associated with erythrocytosis may be hypomorphic. 42 All these limitations make the classification of the identified variants difficult.…”

Section: Discussionmentioning

confidence: 99%

“…9,[19][20][21][23][24][25][26][27] In particular, studies demonstrated that some PHD2 mutations induce a subtle loss of function, sometimes very close to the wild-type protein. 26 This article describes a collaborative study of 34 novel genetic variants (in addition to 5 previously described 16,19,[28][29][30][31][32][33] ) identified in the EGLN1 gene using next-generation sequencing panels. The study includes data from sequencing of a total of 2,160 patients with hereditary or idiopathic erythrocytosis recruited in seven European countries.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis

et al. 2023

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Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis

et al. 2023

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“…The age of the patient was not reported but there were no thrombotic events. The authors suggested that more studies were required to better understand genotype-phenotype correlations ( 10 ). In our Turkish family with the EPOR mutation, the highest Hb was 23 g/dL in the male sibling and 20.4 g/dL in the female sibling.…”

Section: Discussionmentioning

confidence: 99%

EPOR mutasyonuna bağlı konjenital eritrositozu olan Türk ailenin klinik özellikleri. Çocuk ve ergenlerde düzenli flebotomi gereklimidir?

2019

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Here we present two siblings, a 9-year-old boy and a 15-year-old girl at presentation, with congenital erythrocytosis due to an EPOR c.1316G>A (p.Trp439Term) mutation. The patients had nausea, abdominal pain, and headache when they presented with hemoglobin levels of 23 g/dL and 19.4 g/dL, respectively. Their father, paternal uncle, and probably the paternal aunt and grandmother had congenital erythrocytosis. The siblings generally preferred to visit hospital when hyperviscosity symptoms developed and had intermittent phlebotomies. Their compliance to anti-aggregant and hematinic treatment was not satisfactory. Within the 11-year follow-up period, the siblings had no thrombohemorrhagic complications, whereas their 39-year-old uncle had a stroke. In addition to antiaggregant treatment, phlebotomy during hyperviscosity symptoms may be safe in children and adolescents; routine phlebotomies may be recommended to adults to prevent thrombohemorrhagic complications.

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“…This observed loss of heterozygosity suggests that PHD2 plays a tumor suppressor role in chromaffin cells and the closely related paraganglia cells that are transformed in paraganglioma. Other reports of PHD2 mutation in polycythemia note that patients inherit a single mutated allele ( Percy et al, 2006 ; Percy et al, 2007 ; Barradas et al, 2018 ). This could imply that haploinsufficiency of wild-type PHD2 might be enough to induce symptoms.…”

Section: Limited Evidence For Non-hif Characteristics Of Vhl Diseasementioning

confidence: 99%

Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata

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et al. 2022

eLife

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von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome. Certain mutations in pVHL have been determined to be causative of VHL disease through the disruption of HIFα degradation. However, it remains a focus of investigation and debate whether the disruption of HIFα degradation alone is sufficient to explain the complex genotype-phenotype relationship of VHL disease or whether the other lesser or yet characterized substrates and functions of pVHL impact the development of the VHL disease stigmata; the elucidation of which would have a significant ramification to the direction of research efforts and future management and care of VHL patients and for those manifesting sporadic counterparts of VHL disease. Here, we examine the current literature including the other emergent pseudohypoxic diseases and propose that the VHL disease-phenotypic spectrum could be explained solely by the varied disruption of HIFα signaling upon the loss or mutation in pVHL.

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Congenital erythrocytosis – discover of a new mutation in the EGLN1 gene

Cited by 5 publications

References 8 publications

Characterization of genetic variants in the <i>EGLN1/PHD2</i> gene identified in a European collection of patients with erythrocytosis

Characterization of genetic variants in the <i>EGLN1/PHD2</i> gene identified in a European collection of patients with erythrocytosis

EPOR mutasyonuna bağlı konjenital eritrositozu olan Türk ailenin klinik özellikleri. Çocuk ve ergenlerde düzenli flebotomi gereklimidir?

Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata

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