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Analysis of deletional hereditary persistence of fetal hemoglobin/??-thalassemia and ?-globin gene mutations in Southerwestern China.

ABSTRACT: BACKGROUND:Deletional hereditary persistence of fetal hemoglobin (HPFH)/??-thalassemia and ?-thalassemia are rare inherited disorders which may complicate the diagnosis of ?-thalassemia. The aim of this study was to reveal the frequency of these two disorders in Southwestern China. METHODS:A total of 33,596 subjects were enrolled for deletional HPFH/??-thalassemia, and positive individuals with high fetal hemoglobin (Hb F) level were diagnosed by multiplex ligation-dependent probe amplification (MLPA). A total of 17,834 subjects were analyzed for mutations in the ?-globin gene. Positive samples with low Hb A2 levels were confirmed by ?-globin gene sequencing. Furthermore, the pathogenicity and construction of a selected ?-globin mutation were analyzed. RESULTS:A total of 92 suspected cases with Hb F ?5.0% were further characterized by MLPA. Eight different deletional HPFH/??-thalassemia were observed at a frequency of 0.024%. In addition, 195 cases suspected to have a ?-globin gene mutation (Hb A2 ?2.0%) were characterized by molecular analysis. ?-Globin gene mutation was found at a frequency of 0.49% in Yunnan. The pathogenicity and construction for a selected ?-globin mutation was predicted. CONCLUSION:Screening of these two disorders was analyzed in Southwestern China, which could define the molecular basis of these conditions in this population.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6565566 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Analysis of deletional hereditary persistence of fetal hemoglobin/δβ-thalassemia and δ-globin gene mutations in Southerwestern China.

Zhang Jie J Yang Yang Y Li Peng P Yan Yuanlong Y Lv Tao T Zhao Tingting T Zeng Xiaohong X Li Dongmei D Zhou Xiaoyan X Chen Hong H Su Jie J Yang Tonghua T He Jing J Zhu Baosheng B

Molecular genetics & genomic medicine 20190501 6

<h4>Background</h4>Deletional hereditary persistence of fetal hemoglobin (HPFH)/δβ-thalassemia and δ-thalassemia are rare inherited disorders which may complicate the diagnosis of β-thalassemia. The aim of this study was to reveal the frequency of these two disorders in Southwestern China.<h4>Methods</h4>A total of 33,596 subjects were enrolled for deletional HPFH/δβ-thalassemia, and positive individuals with high fetal hemoglobin (Hb F) level were diagnosed by multiplex ligation-dependent probe ...[more]

PMID: 31044540

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Project description:Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain β-thalassemias. Normal levels of fetal hemoglobin postnatally are approximately 1% of total hemoglobin. Patients who have hereditary persistence of fetal hemoglobin, characterized by elevated synthesis of γ-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by β-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or γ-globin gene promoter point mutations (non-deletional hereditary persistence of fetal hemoglobin). Current research has focused on elucidating the pathways involved in the maintenance/reactivation of γ-globin in adult life. To better understand these pathways, we generated new β-globin locus yeast artificial chromosome transgenic mice bearing the (A)γ-globin -175 T > C or -195 C > G hereditary persistence of fetal hemoglobin mutations to model naturally occurring hereditary persistence of fetal hemoglobin. Adult -175 and -195 mutant β-YAC mice displayed a hereditary persistence of fetal hemoglobin phenotype, as measured at the mRNA and protein levels. The molecular basis for these phenotypes was examined by chromatin immunoprecipitation of transcription factor/co-factor binding, including YY1, PAX1, TAL1, LMO2, and LDB1. In -175 HPFH versus wild-type samples, the occupancy of LMO2, TAL1 and LDB1 proteins was enriched in HPFH mice (5.8-fold, 5.2-fold and 2.7-fold, respectively), a result that concurs with a recent study in cell lines showing that these proteins form a complex with GATA-1 to mediate long-range interactions between the locus control region and the (A)γ-globin gene. Both hereditary persistence of fetal hemoglobin mutations result in a gain of (A)γ-globin activation, in contrast to other hereditary persistence of fetal hemoglobin mutations that result in a loss of repression. The mice provide additional tools to study γ-globin gene expression and may reveal new targets for selectively activating fetal hemoglobin.

Project description:BACKGROUND:Individuals with ??-thalassemia/HPFH and ?-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/??-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. METHODS:A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level???5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) was used to screen for ?-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene was performed for all those subjects. RESULTS:A total of 654 individuals had hemoglobin (HbF) levels?5, and 0.12% of the couples were found to be heterozygous for HPFH/??-thalassemia, including Chinese G? (A???)0-thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore-Boston-Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying ?-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 55cases of nondeletional-HPFH (nd-HPFH), including 54 with Italian nd-HPFH and one with the A?-197C-T heterozygous state. It is difficult to discriminate between Chinese G? (A???)0-thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. CONCLUSIONS:This study is the first to describe the familial prevalence of HPFH/??-thalassemia and the high-risk rate in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We also presented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for ?-thalassemia intermedia.

Project description:Increase of the expression of ?-globin gene and high production of fetal hemoglobin (HbF) in ?-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify ?-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea).A?-globin gene sequencing was performed on genomic DNA isolated from a total of 75 ?-thalassemia patients, including 31 ?039/?039, 33 ?039/?+IVSI-110, 9 ?+IVSI-110/?+IVSI-110, one ?0IVSI-1/?+IVSI-6 and one ?039/?+IVSI-6.The results show that the rs368698783 polymorphism is present in ?-thalassemia patients in the 5'UTR sequence (+25) of the A?-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This A?(+25 G->A) polymorphism is associated with the G?-globin-XmnI polymorphism and both are linked with the ?039-globin gene, but not with the ?+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the A?(+25 G->A) and G?-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from ?039/?039 thalassemia patients.As a potential explanation of our findings, we hypothesize that in ?-thalassemia the G?-globin-XmnI/A?-globin-(G->A) genotype is frequently under genetic linkage with ?0-thalassemia mutations, but not with the ?+-thalassemia mutation here studied (i.e. ?+IVSI-110) and that this genetic combination has been selected within the population of ?0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the A?-globin gene associated in ?039 thalassemia patients with high HbF in erythroid precursor cells.

Dataset Information

Analysis of deletional hereditary persistence of fetal hemoglobin/??-thalassemia and ?-globin gene mutations in Southerwestern China.

Publications

Analysis of deletional hereditary persistence of fetal hemoglobin/δβ-thalassemia and δ-globin gene mutations in Southerwestern China.

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