Genetic basis of unexplained erythrocytosis in Indian patients

Mallik, Nabhajit; Sharma, Prashant; Hira, Jasbir Kaur; Chhabra, Sanjeev; Sreedharanunni, Sreejesh; Kumar, Narender; Naseem, Shano; Sachdeva, Man Updesh Singh; Ahluwalia, Jasmina; Malhotra, Pankaj; Varma, Neelam; Varma, Subhash; Das, Reena

doi:10.1111/ejh.13267

Cited by 16 publications

(22 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two other high oxygen affinity variants having substitution in the same position are also described in the literature, namely Hb Barcelona [β 94(FG1)Asp→His] and Hb Bunbury [β 94(FG1)Asp→Asn] 20 . In our study of 18 North Indian CE patients, 3 had high oxygen affinity hemoglobins—1 having a heterozygous Hb McKees Rocks HBB :c.438T>A (p.Tyr146*), and 2 brothers having Hb Rainier HBB :c.437A>G (p.Tyr146Cys) 21 …”

Section: Secondary Congenital Erythrocytosissupporting

confidence: 55%

See 1 more Smart Citation

Congenital erythrocytosis

Mallik

Das

Malhotra

et al. 2021

European J of Haematology

Self Cite

View full text Add to dashboard Cite

Erythrocytosis, or increased red cell mass, may be labeled as primary or secondary, depending on whether the molecular defect is intrinsic to the red blood cells/their precursors or extrinsic to them, the latter being typically associated with elevated erythropoietin (EPO) levels. Inherited/congenital erythrocytosis (CE) of both primary and secondary types is increasingly recognized as the cause in many patients in whom acquired, especially neoplastic causes have been excluded. During the past two decades, the underlying molecular mechanisms of CE are increasingly getting unraveled. Gain‐in‐function mutations in the erythropoietin receptor gene were among the first to be characterized in a disorder termed primary familial and congenital polycythemia. Another set of mutations affect the components of the oxygen‐sensing pathway. Under normoxic conditions, the hypoxia‐inducible factor (HIF), upon hydroxylation by the prolyl‐4‐hydroxylase domain protein 2 (PHD2) enzyme, is degraded by the von Hippel‐Lindau protein. In hypoxic conditions, failure of prolyl hydroxylation leads to stabilization of HIF and activation of the EPO gene. CE has been found to be caused by loss‐of‐function mutations in VHL and PHD2/EGLN1 as well as gain‐of‐function mutations in HIF‐2α (EPAS1), all resulting in constitutive activation of EPO signaling. Apart from these, globin gene mutations leading to formation of high oxygen affinity hemoglobins also cause CE. Rarely, bisphosphoglycerate mutate mutations, affecting the 2,3‐bisphosphoglycerate levels, can increase the oxygen affinity of hemoglobin and cause CE. This narrative review examines the current mutational spectrum of CE and the distinctive pathogenetic mechanisms that give rise to this increasingly recognized condition in various parts of the world.

show abstract

Section: Secondary Congenital Erythrocytosissupporting

confidence: 55%

“…We recently reported 18 patients from 15 North Indian families presenting with unexplained erythrocytosis using focused Sanger sequencing. Eleven patients from nine families were homozygous for VHL :c.598C>T (p.Arg200Trp), making it a recurrent genetic abnormality in the north Indian population 21 …”

Section: Secondary Congenital Erythrocytosismentioning

confidence: 99%

Congenital erythrocytosis

Mallik

Das

Malhotra

et al. 2021

European J of Haematology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Genetic mutations in the erythropoiesis and hypoxia sensing pathways have been detected in upto 20% patients of IE [21]. Studies, including one from India suggest that patients with EPO level below normal may be screened for mutations involving the EPO signalling pathway (EPOR exon 7-8) while those with an inappropriately normal EPO level with respect to their Hb may be screened for mutations in the oxygen sensing pathway (VHL, PHD2, HIF2a, b globin and a globin gene) [22,23].…”

Section: Discussionmentioning

confidence: 99%

Dissecting Primary Erythrocytosis Among Polycythemia Patients Referred to an Indian Armed Forces Hospital

Khurana

Lakshman

Kumar

et al. 2019

Indian J Hematol Blood Transfus

View full text Add to dashboard Cite

Referrals for evaluation of polycythemia cases have increased since the hemoglobin (Hb) thresholds for diagnosis of Polycythemia Vera (PV) have been lowered by WHO. The current study enrolled patients of age [ 18 years from the Indian Armed Forces or their family members with polycythemia from November 2016 to October 2018. After exclusion of secondary causes, 49 patients were diagnosed as Primary Erythrocytosis (PE). The patients were classified into two groups: PV and Idiopathic Erythrocytosis (IE) and a systematic comparison of clinical and laboratory features of the two groups was done. The prevalence of PV in PE was 20.4% (10 of 49) while the rest 39 (79.6%) had IE. Seven PV patients had JAK2 V617F mutation, one had JAK2 Exon12 mutation, and two were JAK2 negative PV. Nine of 10 (90%) PV patients had Hb [ 18.5 g/dl, while only 21 of 39 (53.8%) IE patients had Hb [ 18.5 g/dl (p = 0.06). None of the JAK2 mutated patients had Hb \ 18.5 g/dl. We conclude that PV is more prevalent in patients of PE with Hb [ 18.5 g/dl. Most patients with Hb between 16.5-18.5 g/dl would still be classified as IE. We advocate the need for further studies evaluating the utility of investigating all patients of PE with the revised WHO Hb threshold as well as studies on genetic profile of IE patients from India.

show abstract

“…Clinical laboratories that lack facilities for oxygen-saturation curve analysis may calculate the p50 mathematically using venous blood gas analysis parameters 3. Genetic confirmation is often also straightforward using direct DNA sequencing of the relatively small globin genes by Sanger’s method 1 4 5…”

mentioning

confidence: 99%

“…High oxygen-affinity Hb’s are uncommon causes of congenital erythrocytosis 1 4–6. A prior Indian study found that 3 out of 18 patients with congenital erythrocytosis (including two brothers) had high oxygen affinity variants—Hb McKees Rocks and Hb Rainier 4.…”

mentioning

confidence: 99%