Bravo-Urquiola Martha, Arends Anabel, Gómez Gilberto, Montilla Silvia, Gerard Nathalie, Chacin Marycarmen, Berbar Tsouria, García Odalis, García Gloria, Velasquez Dalia, Castillo Omar, Krishnamoorthy Rajagopal
Laboratorio de Investigación de Hemoglobinas Anormales, Hospital Universitario de Caracas and Instituto Anatómico José Izquierdo, Universidad Central de Venezuela , Caracas , Venezuela.
Hemoglobin. 2012;36(3):209-18. doi: 10.3109/03630269.2012.674997.
In order to establish the spectrum of β-thalassemia (β-thal) mutations in the Venezuelan population for the first time, 127 unrelated subjects either with a suspicion of β-thal trait or with a clinically recognized β-thal syndrome of different degrees of severity, were studied. DNA from these subjects was analyzed by a polymerase chain reaction (PCR)-based reverse dot-blot method or amplification refractory mutation system (ARMS). Prototype β-globin gene sequencing of relevant DNA was performed to confirm the mutations. Fifteen different mutations were identified accounting for 92.0% of the mutant alleles explored, revealing a significant genetic heterogeneity at the β-globin gene locus in this population. The most frequent mutations were codon 39 (C >T) 34.1%, IVS-I-1 (G >A) 11.1%, IVS-I-6 (T > C) 6.6%, IVS-I-110 (G >A) 6.6%, IVS-II-849 (A >G) 6.6%, -88 (C >T) 6.0%, -29 (A >G) 5.2%, followed by the less common IVS-I-5 (G >A) 3.7%, the 1,393 bp deletion 3.0%, IVS-II-1 (G >A) 3.0%, -86 (C >G) 2.2%, IVS-II-1 (G >T) 1.5%, codons 41/42 (-TCTT) 1.5%, IVS-II-745 (C >G) 0.7% and deletional δβ-thal 0.7%. Overall, these data demonstrate that the major sources of β-thal alleles in Venezuela, as expected, are of Mediterranean and African origins. This is the first large study defining the molecular spectrum of β-thal in the highly admixed population of Venezuela and lays the foundation for genetic counseling as well as implementing comprehensive clinical care programs. Diversity of haplotypes associated with some of the β-thal mutations can be explained by in situ recombination events in Venezuela.
为首次确定委内瑞拉人群中β地中海贫血（β-地贫）突变谱，我们研究了127名无亲缘关系的受试者，这些受试者要么疑似携带β-地贫特征，要么患有临床诊断的不同严重程度的β-地贫综合征。采用基于聚合酶链反应（PCR）的反向点杂交法或扩增阻滞突变系统（ARMS）分析这些受试者的DNA。对相关DNA进行β-珠蛋白基因原序列测序以确认突变。共鉴定出15种不同突变，占所检测突变等位基因的92.0%，揭示了该人群β-珠蛋白基因位点存在显著的遗传异质性。最常见的突变是密码子39（C>T）34.1%、IVS-I-1（G>A）11.1%、IVS-I-6（T>C）6.6%、IVS-I-110（G>A）6.6%、IVS-II-8（A>G）6.6%、-88（C>T）6.0%、-29（A>G）5.2%，其次是较罕见的IVS-I-5（G>A）3.7%、1393bp缺失3.0%、IVS-II-（G>A）3.0%、-86（C>G）2.2%、IVS-II-（G>T）1.5%、密码子41/42（-TCTT）1.5%IVS-II-745（C>G）0.7%和缺失型δβ地贫0.7%。总体而言，这些数据表明，正如预期的那样，委内瑞拉β-地贫等位基因的主要来源是地中海和非洲血统。这是第一项在高度混合的委内瑞拉人群中定义β-地贫分子谱的大型研究，为遗传咨询以及实施全面的临床护理计划奠定了基础。与某些β-地贫突变相关的单倍型多样性可通过委内瑞拉的原位重组事件来解释。
