A novel gain-of-function PIP4K2A mutation elevates the expression of β-globin and aggravates the severity of α-thalassemia.
PIP4K2A
Hb H disease
erythroid differentiation
gain-of-function mutation
terminal enucleation
β-globin
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
21
06
2023
received:
22
03
2023
accepted:
26
06
2023
medline:
1
9
2023
pubmed:
10
7
2023
entrez:
9
7
2023
Statut:
ppublish
Résumé
Haemoglobin H (Hb H) disease (intermediate status of α-thalassemia) shows marked phenotypic variability from asymptomatic to severe anaemia. Apart from the combined β-thalassemia allele ameliorating clinical severity, reports of genetic modifier genes affecting the phenotype of Hb H disease are scarce which bring inconvenience to precise diagnosis and genetic counselling of the patients. Here, we present a novel mutation (c.948C>A, p.S316R) in the PIP4K2A gene in a female Hb H disease patient who displayed moderate anaemia and a relatively high Hb H level. Haematological analysis in her family members revealed that individuals carrying this mutation have upregulated β-globin expression, leading to a more imbalanced β/α-globin ratio and more Hb H inclusion bodies in peripheral red blood cells. According to functional experiments, the mutant PIP4K2A protein exhibits enhanced protein stability, increased kinase activity and a stronger regulatory effect on downstream proteins, suggesting a gain-of-function mutation. Moreover, introduction of the S316R mutation into HUDEP-2 cells increased expression of β-globin, further inhibiting erythroid differentiation and terminal enucleation. Thus, the S316R mutation is a novel genetic factor associated with β-globin expression, and the PIP4K2A gene is a new potential modifier gene affecting the α-thalassemia phenotype.
Substances chimiques
beta-Globins
0
PIP4K2A protein, human
EC 2.7.1.-
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1018-1023Informations de copyright
© 2023 British Society for Haematology and John Wiley & Sons Ltd.
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