Shandong
S
0.08% (1/1190)
c.41T>C 1
Guangdong Thalassemic endemic region, n=3839
1.25% (48/3839)
Guangxi
c.519_525dupCGGCGCC 36
c.895C>G 9
c.13G>A
1
c.892G>C 1
NA
1.000
Damaging
1 (1.6%)

NA
1 (1.6%)

1.000
Damaging
1 (1.6%)

携带KLF1突变的正常个体的 MCV 和 MCH 值降低
KLF1突变携带者及KLF1突变复合地贫 个体的HbA2 和 HbF 水平升高
Normal Individuals
-Thalassemia Trait
–/–
A/C
T/T
P2 9/M 4
None (0)
Occasional (1)
87
5.8 82.0 / -28 / CD41/42
[c.519_525dupC GGCGCC]+[=]
–/–
A/C
T/T
P3† 8/M
3
Occasional (8)
Systematic (8-12)*
86
c.1022G>A 1
Blood, 2014.
中国南方人群的KLF1突变谱
突变
c.519_525dup CGGCGCC c.895C>G c.1022G>A c.13G>A c.892G>C c.913+1G>A c.1001C>G
AA 变异
位点 类型
p.Gly176Ala fsX179
p.His299Asp
N (%)
CD44
NA
0.000
Damaging
0.00
Damaging
0.040
Damaging
0.000
Damaging
NA
0.00
Damaging
NA
48 (75.0%)

1.000
Damaging
10
(15.6%)

1.000
Damaging
2 (3.1%)

0.977
Damaging
1 (1.6%)
地中海贫血 (地贫)
-地中海贫血
人-珠蛋白基因突变使-珠蛋白肽链合成减少或 丧失而导致的遗传性溶血性贫血 (OMIM: #604131)
HBA2: OMIM 141850; HBA1: OMIM +141800
-地中海贫血
人-珠蛋白基因突变使 -珠蛋白肽链合成减少或 丧失而导致的遗传性溶血性贫血 (OMIM: #613985)
中间型地贫: 地贫复合地贫
成员
Hb MCV MCH HbA2 HbF (g/L) (fL) (pg) (%) (%)
地贫
I2: 父亲
129 69.4 21.2 5.3 ─ CD17 / N
I1: 母亲
100 64.8 20.1 4.7 ─ IVS-Ⅱ-654 / N
II1: 先证者
66
HbF
(%)HBA genotypeHBB genotype
KLF1
genotype
HBG2
(XmnI)
BCL11 A
rs766
HBS1LMYB
rs939
P1 9/M 4
None (0)
Occasional (1)
88 5.4 82.2 / -28 / -28
[c.519_525dupC GGCGCC]+[=]
遗传修饰基因与地中海贫血表型
Chengdu, June 21，2016
徐湘民
南方医科大学基础医学院 南方医院产前诊断与遗传病诊断技术中心 广东省出生缺陷监测与干预重点实验室
和地贫广泛分布于世界热带和亚热带
中国南方高发地区 人群携带率3%-24%
Blood Rev, 2012.
-和-地中海贫血的概况
人类-珠蛋白基因组织结构
人类-珠蛋白基因组织结构
Br J Haematol. 1995. Hum Genet. 1996. Am J Hematol. 2000. Haematologica. 2001; 2003. J Clin Pathol. 2004; 2004; 2005. Ann Hematol. 2007; 2011. Blood Cells Mol Dis. 2008; 2010; 2013. Hemoglobin. 2010. BMC Med Genet. 2010. Clin Genet. 2013; 2014.
Hb F / Clinical data
Hb F associated SNPs
HBG2 (rs7482144) BCL11A (rs766432)
HBS1L-MYB (rs9399137)
中国南方地贫高发区的KLF1突变 发生率明显高于北方地区
China
N
Non-thalassemic endemic region, n=1190
KLF1
-Thalassemia
KLF1突变群体遗传学分析
Non-thalassemia endemic region
Population samples (n=5029)
North China (n=1190)
South China (n=3839)
N/ N + / (n=1971) M/ N (n=946)
3.5
44.7
/
CD41/42 / CD41/42
[c.519_525dupC GGCGCC]+[=]
–/–
A/A
T/T
P4† 11/F 4
None (0)
Systematic (8–12)*
90
4.0 56.6 / CD17 / CD41/42
[c.519_525dupC GGCGCC]+[=]
–/–
A/C
T/T
P5† 14/F
2
Occasional (1)
Occasional (3-4)
83
4.7 48.1 / CD17 / CD41/42
[c.519_525dupC GGCGCC]+[=]
–/–
A/C
T/T
P6† 9/M
3
Occasional (7)
Systematic (8–12)*
Exon2 Exon2
Frameshift Missense
p.Cys341Tyr
Exon3
Missense
p.Glu5Lys
Exon1
Missense
p.Ala298Pro Exon2
Missense
NA
Intron2
Splicing
p.Thr334Arg Exon3
Missense
功能预测 SIFT PolyPhen-2
“Reduction of -globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.”
91 3.4 13.2 / CD17 / CD17
[c.519_525dupC GGCGCC]+[=]
–/–
A/A
T/T
P7† 9/M
2.5
Occasional (1)
Occasional (1)
71
12例携带KLF1突变的-地贫患者的临床和实验室资料
临床指标
血液标学指
基因型
ID
Age
(y/Sex)
Onset (y)
Number of transfusions /y (<4 years )
Number of transfusions /y(at present )
Hb HbA
(g/L) (%2)
Thalassemia endemic region
M/ M (n=922)
Phenotypic analysis
Genotypic analysis
CD44 / Hb F
KLF1 gene
MCV/MCH/Hb A2/Clinical data - and -globin genes
KLF1在红细胞生成中的多功能性及其作用机制
MEP
KLF1 Terminal differentiation
Cell cycle regulation
S
G2
G1
M 红系发育和分化
红细胞终末成熟
珠蛋白转换调节
Blood, 2008; 2011.
假设:
检验可升高HbF的红系转录因子— KLF1 突变是否存在： （1）与-地贫发生相关的频率地域差异？ （2）与-地贫表型相关的潜在修饰作用？
中间型地贫: 地贫复合珠蛋白基因三联体
基因型