| RRC ID |
77249
|
| Author |
Zhang Y, Xie H, Liang G, Qin Y, Wei X, Ning S, Liang Y, Liang X, Xie Y, Lin Z, Zhu D, Lin J, Xiong F, Xu X, Shang X.
|
| Title |
A novel gain-of-function PIP4K2A mutation elevates the expression of β-globin and aggravates the severity of α-thalassemia.
|
| Journal |
Br J Haematol
|
| Abstract |
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.
|
| Volume |
202(5)
|
| Pages |
1018-1023
|
| Published |
2023-9-1
|
| DOI |
10.1111/bjh.18967
|
| PMID |
37423903
|
| MeSH |
Female
Gain of Function Mutation
Humans
Mutation
Phenotype
Phosphotransferases (Alcohol Group Acceptor) / genetics
alpha-Thalassemia* / genetics
beta-Globins / genetics
beta-Thalassemia* / genetics
|
| IF |
5.518
|
| Resource |
| Human and Animal Cells |
HUDEP-2(RCB4557) |
