Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster

α-Globin as a molecular target in the treatment of β-thalassemia

Thalassaemia and sickle cell disease have been recognized by the World Health Organization as important inherited disorders principally impacting on the populations of low income countries. To create a national and regional profile of β-thalassaemia mutations in the population of India, a meta-analysis was conducted on 17 selected studies comprising 8,505 alleles and offering near-national coverage for the disease. At the national level 52 mutations accounted for 97.5% of all β-thalassaemia alleles, with IVSI-5(G>C) the most common disease allele (54.7%). Population stratification was apparent in the mutation profiles at regional level with, for example, the prevalence of IVSI-5(G>C) varying from 44.8% in the North to 71.4% in the East. A number of major mutations, such as Poly A(T>C), were apparently restricted to a particular region of the country, although these findings may in part reflect the variant test protocols adopted by different centres. Given the size and genetic complexity of the Indian population, and with specific mutations for β-thalassaemia known to be strongly associated with individual communities, comprehensive disease registries need to be compiled at state, district and community levels to ensure the efficacy of genetic education, screening and counselling programmes. At the same, time appropriately designed community-based studies are required as a health priority to correct earlier sampling inequities which resulted in the under-representation of many communities, in particular rural and socioeconomically under-privileged groups.

https://link.springer.com/content/pdf/10.1007%2Fs11568-010-9132-3.pdf

Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes

Fetal hemoglobin (HbF), the predominant hemoglobin in the fetus, is a mixture of two molecular species (alpha(2)(G)gamma(2) and alpha(2)(A)gamma(2)) that differ only at position 136 reflecting the products of two nonallelic gamma-globin genes. At the time of birth, HbF accounts for approximately 70% of the total Hb. The (G)gamma:(A)gamma globin ratio in the HbF of normal newborn is 70:30 whereas in the trace amounts of HbF that is found in the adult it reverses to 40:60 because of a gamma- to beta-globin gene switch. Alterations of these ratios are indicative of a molecular defect at the level of the HbF synthesis. Qualitative hemoglobinopathies due to (G)gamma and (A)gamma chain structural variants, and quantitative hemoglobinopathies affecting the synthesis of HbF such as gamma-thalassemias, duplications, triplications, and even sextuplications of the gamma-globin genes, which may be detected in newborn blood lysates, have been described. Moreover, several pathological and nonpathological conditions affecting the beta-globin gene cluster, such as beta-thalassemia, sickle cell disease, deltabeta-thalassemia, and hereditary persistence of HbF syndromes, are characterized by the continued synthesis of gamma-globin chains in the adult life. Studies of these natural mutants associated with increased synthesis of HbF in adult life have provided considerable insight into the understanding of the control of globin gene expression and Hb switching.

https://iubmb.onlinelibrary.wiley.com/doi/pdf/10.1002/iub.4

Disorders of the synthesis of human fetal hemoglobin.

Hectd1 mutant mouse embryos exhibit the neural tube defect exencephaly associated with abnormal cranial mesenchyme. Cellular rearrangements in cranial mesenchyme are essential during neurulation for elevation of the neural folds. Here we investigate the molecular basis of the abnormal behavior of Hectd1 mutant cranial mesenchyme. We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Extracellular Hsp90 enhances migration of multiple cell types. In mutant cranial mesenchyme cells, both secretion of Hsp90 and emigration of cells from cranial mesenchyme explants were enhanced. Importantly, we show that this enhanced emigration was highly dependent on the excess Hsp90 secreted from mutant cells. Together, our data set forth a model whereby increased secretion of Hsp90 in the cranial mesenchyme of Hectd1 mutants is responsible, at least in part, for the altered organization and behavior of these cells and provides a potential molecular mechanism underlying the neural tube defect.

https://rupress.org/jcb/article-pdf/196/6/789/1355006/jcb_201105101.pdf

Hectd1 regulates intracellular localization and secretion of Hsp90 to control cellular behavior of the cranial mesenchyme

Sixty-four thalassemia and E-β thalassemia patients were studied for factors that modulate the severity of the disease; i. e., mutation of β-globin gene, presence of α-deletion, and presence of an XnmI site at the −158 position of the Gγ gene. Presence of α-deletion and/or homozygosity for the XmnI site was in general associated with less-severe disease. About 12% of the patients harbored single α-gene deletion, and the gene frequency of the XnmI polymorphism in these patients is 0.48.

Variable severity of β-thalassemia patients of Eastern India: effect of α-thalassemia and XmnI polymorphism

Objective
To control the birth of thalassemic children in India.

Methods
Mutations present in the population of eastern India and in carrier parents seeking prenatal diagnosis were detected by the PCR-based technique of ARMS (amplification refractory mutation system) or gap-PCR. To screen for maternal tissue contamination in CVS, haplotypes associated with the β-globin gene clusters were constructed using six polymorphic restriction sites. Prenatal diagnosis was accomplished by checking presence of parental mutation in the DNA from chorionic villus sampling (CVS) collected at 8 to 10 weeks' gestation by appropriate technique.

Results
Six hundred and fifty (650) unrelated β-thalassemia chromosomes were screened for 11 common mutations to characterize the mutation distribution in this population. Starting from early 2000, 63 families from different parts of West Bengal and from surrounding areas have been offered prenatal counseling for β-thalassemia.

Conclusion
The population of this region is conscious and willing to accept prenatal diagnosis as a means of control of thalassemia. Copyright © 2004 John Wiley & Sons, Ltd.

Profile of β-thalassemia in eastern India and its prenatal diagnosis

OBJECTIVE To correlate different polymorphisms of the beta-globin cluster with fetal hemoglobin (HbF) level in beta-thalassemia and E-beta thalassemia patients. METHODS Fifteen thalassemia patients, seven with high HbF and not requiring transfusion, eight with lower HbF and requiring transfusion were studied for beta-globin mutation, concurrent inheritance of alpha-thalassemia, RFLP haplotype, a C-->T polymorphism at -158 of Ggamma and configuration of an (AT)(x)T(y) motif at -540 of beta-globin gene. RESULTS Senegal 5'beta-haplotype and the polymorphism at -158 of G(gamma) was (P = 0.063) was linked to the high-HbF phenotype but the (AT)(9)T(5) configuration of the (AT)(x)T(y) motif was not (P = 0.6). Study of 30 chromosomes revealed 7 different configurations of the (AT)(x)T(y) motif. Association of these motifs with specific beta-globin mutations of this region has also been determined. CONCLUSION The senegal haplotype and the polymorphism at -158 of G(gamma) was linked to the high-HbF phenotype.

Two β‐globin cluster‐linked polymorphic loci in thalassemia patients of variable levels of fetal hemoglobin

A new matrix-vector multiplication technique is proposed where free-space optical interconnections are used. The multiplication is carried out by a convolution technique where one set of numbers (multiplicands) is represented by the on/off states of light sources and the other sets of numbers (the multiplier) are recorded in matrix form on a spatial light modulator. The partial products are recorded on a detector array which, when added by a microprocessor, yield the respective convolution coefficients. No analogue to digital conversion electronics are necessary in the proposed technique and instead only a thresholding circuit is used. Compared to other existing techniques, the processing time is also reduced in the proposed system.

Sanmay Bandyopadhyay

Papers

Variable severity of β-thalassemia patients of Eastern India: effect of α-thalassemia and XmnI polymorphism

Profile of β-thalassemia in eastern India and its prenatal diagnosis

Two β‐globin cluster‐linked polymorphic loci in thalassemia patients of variable levels of fetal hemoglobin

Realization of digital optical matrix-vector multiplication