Eunice Sindhuvi Edison

Iron homeostasis: new players, newer insights

Although iron is a relatively abundant element in the universe, it is estimated that more than 2 billion people worldwide suffer from iron deficiency anemia. Iron deficiency results in impaired production of iron‐containing proteins, the most prominent of which is hemoglobin. Cellular iron deficiency inhibits cell growth and subsequently leads to cell death. Hemochromatosis, an inherited disorder results in disproportionate absorption of iron and the extra iron builds up in tissues resulting in organ damage. As both iron deficiency and iron overload have adverse effects, cellular and systemic iron homeostasis is critically important. Recent advances in the field of iron metabolism have led to newer understanding of the pathways involved in iron homeostasis and the diseases which arise from alteration in the regulators. Although insight into this complex regulation of the proteins involved in iron homeostasis has been obtained mainly through animal studies, it is most likely that this knowledge can be directly extrapolated to humans.

Analysis of β globin mutations in the Indian population : presence of rare and novel mutations and region-wise heterogeneity

β Thalassaemia is a major public health problem in India. A comprehensive database of the spectrum of mutations causing β thalassaemia in the Indian population is necessary. This study in which a large number of patients with β thalassaemia including those from certain regions that were not explored earlier shows a great heterogeneity of mutations. Several novel and rare alleles that have not been reported earlier in the Indian population have been identified, and mutations differ in frequency in different regions of the country. This information on the spectrum of mutations has implications for the control of β thalassaemia in a population with complex ethnic background and also on the genotype–phenotype correlation of the disease.

Rapid Detection of β-Globin Gene Mutations and Polymorphisms by Temporal Temperature Gradient Gel Electrophoresis

Background: Inherited hemoglobin disorders represent the most common Mendelian disease worldwide. Prevention programs based on molecular diagnosis of heterozygous carriers and/or patients require the use of reliable mutation scanning methods in at-risk populations. Methods: We developed a rapid and highly specific mutation-screening test based on temporal temperature gradient gel electrophoresis (TTGE). We analyzed 889 β-thalassemia genes from homozygous β-thalassemia patients and unrelated individuals with heterozygous β-thalassemia. Previously reported common mutations were screened by reverse dot blots using allele-specific probes. The rare mutations were analyzed by TTGE. Results: We found common mutations in 753 β-thalassemia genes. TTGE analysis in the rest of the genes showed the presence of mutations in different regions of the β-globin gene in 134 of them, and these mutations were characterized by DNA sequencing. In the two genes in which mutations were not identified, large deletions spanning β-globin gene were suspected. Conclusions: Compared with other approaches for comprehensive mutation screening, the reported method is rapid, highly sensitive, cost-effective, and suitable for high-throughput screening of a large number of samples.

Compound Heterozygosity for Hb E and Hb Lepore-Hollandia in India; First Report and Potential Diagnostic Pitfalls

A compound heterozygous state of Hb E [β26(B8)Glu→Lys] with Hb Lepore is rare with very few cases reported in the literature. This report describes the first such case from India. The clinical features and hemoglobin (Hb) analysis mimic Hb E-β-thalassemia (thal) but with a mild phenotype. Detection was made possible in this case because DNA analysis gave discrepant results suggestive of homozygous Hb E. As this was inconsistent with the clinical phenotype and Hb analysis, further evaluation was undertaken that confirmed the presence of Hb Lepore. This study shows that cases of Hb E/Lepore may remain undetected unless family studies and/or detailed DNA analyses in patients diagnosed to have Hb E-β-thal are performed

Hb Lepore in the Indian population.

A study of the spectrum of β‐thalassemia mutations in 230 patients with thalassemia major and 90 patients with thalassemia intermedia revealed mutations producing Hb Lepore in four patients. Two were homozygous and two were compound heterozygous for Hb Lepore and β‐thalassemia. Among the six δ β fusion genes found in these four patients five were those producing Hb Lepore‐Hollandia and one producing Hb Lepore‐Washington–Boston. We also describe a possible misdiagnosis in the heterozygous state of Hb Lepore, as Hb Lepore and Hb A2 are not distinctly separated by cation exchange high performance liquid chromatography.

Two novel missense mutations in iron transport protein transferrin causing hypochromic microcytic anaemia and haemosiderosis: molecular characterization and structural implications

This study was supported in part by a grant BT/PR-13968/MED/12/465/2010 from the Department of Biotechnology, Government of India to ES and by the grant SAF2012-40106 from the Spanish Secretary of Research, Development and Innovation (MINECO) and the grant CIVP16A1857 “Ayudas a proyectos de Investigacion en Ciencias de la Vida- Fundacion Ramon Areces” to M.S. M.S. held a research contract under the Ramon y Cajal program from the Spanish Ministry of Science and Innovation (RYC-2008-02352).

A novel deletion of β-globin promoter causing high HbA2 in an Indian population

β-thalassemia is the most common inherited disorder characterized by a reduction or absence of β-globin chain synthesis. So far, over 200 mutations have been identified that result in β-thalassemia. Most of the mutations are single nucleotide substitutions or deletions, or insertions in the β-

Hb Showa-Yakushiji [β110(G12)Leu→Pro] in Four Unrelated Patients from West Bengal

A T→C mutation in the β-globin gene at codon 110 that produces the hyper unstable variant Hb Showa-Yakushiji, was identified in four unrelated individuals in India. It was found in a compound heterozygous state with other mutations producing β-thalassemia (thal) or Hb E [β26(B8)Glu→Lys]. The mutation producing this abnormal hemoglobin (Hb) was found on the same haplotype in all these patients but differed from the Japanese haplotype, indicating its independent origin in India.

Hyperbilirubinemia in Homozygous HbE Disease Is Associated with the UGT1A1 Gene Polymorphism

Homozygous HbE [β26(B8)Glu → Lys] is a clinically mild disorder with no significant symptoms. However, we have frequently noted hyperbilirubinemia among patients with homozygous HbE in the Indian population, with jaundice being the major complaint at presentation. A study of the UGT1A1 gene polymorphism shows that the variant TA7 in the promoter region of the UGT1A1 gene is associated with hyperbilirubinemia in homozygous HbE patients.

Identification of rare and novel deletions that cause (δβ)0‐thalassaemia and hereditary persistence of foetal haemoglobin in Indian population

Hereditary persistence of foetal haemoglobin (HPFH) and (δβ)0‐thalassaemia are conditions caused by large deletions that involve δ‐ and β‐globin genes in the β‐globin cluster, and they are characterized by increased haemoglobin (HbF) levels in adults. Significant phenotypic diversity is observed between the different mutations that cause these conditions. Molecular characterization of these deletions is important for accurate molecular diagnosis, and they will also provide the information on the cis‐acting genetic regulatory elements present in the β‐globin cluster.