Information Gene HBA2

Information Gene HBA2

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Gene : HBA2? hemoglobin alpha 2 (Homo sapiens)

I don't find any tissues (or organs) in which the expression of this gene is strongest? What is the size of the gene (promoter off) encoding this sequence?

You mention that you "started in bioinformatics", so perhaps you might feel more comfortable taking such an approach to better characterize where the promoter for HBA2 might be.

As @Bitwise mentioned in his comment, "the promoter" is not a well defined region. Often times "we" take the promoter of a gene to be some arbitrary (2-4) kilobytes upstream from the TSS. With more high throughput data coming online (especially from ENCODE), we are starting to get a better picture of where the functional regulatory elements of genes might be.

By combining data from several different high-throughput assays across a variety of cell types, the human genome has been segmented into broad regions of interest. You might start by looking for where the "Predicted promoter region including transcription start site" segment is for HBA2.

I'd also take a closer look at the DNase-seq data in this "promoter region" across as many cell lines as they have processed for you to look for regions that are differentially occupied in hopes of identifying more precisely which parts in the promoter region might be important for the gene's expression (this would, of course, require you to connect DNAseq data with gene expression (RNA-seq) data).

TTR gene

The TTR gene provides instructions for producing a protein called transthyretin. This protein transports vitamin A (retinol) and a hormone called thyroxine throughout the body. To transport thyroxine, four transthyretin proteins must be attached (bound) to each other to form a four-protein unit (tetramer). To transport retinol, transthyretin must form a tetramer and also bind to retinol binding protein. Transthyretin is produced primarily in the liver. A small amount of this protein is produced in an area of the brain called the choroid plexus and in the light-sensitive tissue that lines the back of the eye (the retina).

Treatment for HbH disease varies based on the severity of the symptoms. Many individuals will need a blood transfusion during times of severe illness (crises). This is usually a rare occurrence, and it can be caused by environmental stressors such as fever or exposure to specific medications. Individuals with more severe symptoms may require regular blood transfusions, folic-acid supplementation, antibiotics during certain procedures, iron chelation therapy (removal of excess iron from the body), removal of the spleen, and possibly therapies to increase fetal hemoglobin levels.

Rare cases of survivors with Hb Bart syndrome have been reported when fetal blood transfusions were given, followed by regular treatments similar to those given to individuals with HbH disease. Treatment or surgical correction of birth defects may also be possible. There is a high risk for intellectual and physical disability in these survivors. These individuals may be candidates for hematopoietic stem cell transplantation.

Classification of Genetic Disorders: 2 Types

These are mainly determined by alteration or mutation in the single gene. These disorders are transmitted in next generation according to the principle of inheritance and can be studied by pedigree analysis. These can be dominant or recessive.

For example, Autosomal dominant disorder are Osteogenesis imperfecta, polycystic kidney disease, Huntington’s Disease, Fatal familial Insomnia, etc. Autosomal recessive disorder are Sickle cell anaemia, cystic fibrosis, xeroderma pigmentosum, Albinism etc.

Some of Mendelian disorders are discussed below

It is a sex-linked recessive disease, which is transmitted from an unaffected carrier female to some of the male offsprings. Due to this, patient continues bleeding even on a minor injury because of defective blood coagulation. The gene for haemophilia is located on X-chromosome. The defective alleles produce non-functional proteins, which later form a non-functional cascade of proteins involved in blood clotting.

The possibility of a female becoming a haemophilic is extremely rare because mother of such a female has to be at-least carrier and father should be haemophilic. For example, females suffer from this disease only in homozygous condition, i.e., X C X C . Queen Victoria was a carrier of haemophilia and produced haemophilic individuals.

Colour Blindness:

It is a sex-linked recessive disorder, which results in defect in either red or green cone of eye. It does not mean not seeing any colour at all, in-fact it leads to the failure in discrimination between red and green colour. The gene for colour blindness is present on X-chromosome.

It is more present in males (X C Y) because of the presence of only one X-chromosome as compared to two chromosomes in females. A heterozygous female has normal vision, but is a carrier and passes on the disorder to some of her sons. Colour blindness like any other inheritance show crisscross inheritance.

Sickle-cell Anaemia:

It is an autosome-linked recessive trait that can be transmitted from parents to the offsprings, when both the partners are carrier for the gene (heterozygous).

The disease is controlled by a single pair of allele Hb and Hb . Only the homozygous individuals for Hb S , i.e., Hb S Hb S show the diseased phenotype. The heterozygous individuals are carriers (Hb A Hb S ).

It is caused by the substitution of glutamic acid (Glu) by valine (Val) at the sixth position of the beta globin chain of the haemoglobin molecule.

The mutant haemoglobin molecule undergoes polymerisation under low oxygen tension causing the change in the shape of the RBC from biconcave disc to the elongated sickle like structure.

It is an autosome-linked recessive disease, which occurs due to either mutation or deletion, resulting in reduced rate of synthesis of one of the globin chains of haemoglobin. Anaemia is the main feature of this disease.

Thalassemia is classified into three types on the basis of globin chain affected:

(i) Alpha (α) Thalassemia:

It is controlled by the closely linked genes HBA1 and HBA2 on chromosome 16. In this, the production of globin gene is affected due to the mutation or deletion of one or more of the four alleles.

(ii) Beta (β) Thalassemia:

It is controlled by a single gene HBB on chromosome 11. It occurs due to the mutation in one or both the alleles of the gene. Hence, there is a reduced synthesis of beta globin of haemoglobin.

(iii) Delta (δ) Thalassemia:

As well as alpha and beta chains present in haemoglobin about 3% of adult haemoglobin is made up of alpha and delta chains. Just like beta thalassemia mutations can occur which affect the ability of this gene to produce delta chains.

Phenylketonuria (PKU):

It is an inborn error of metabolism, which is inherited as an autosomal recessive trait. It is a rare disease in which baby is born without the ability to properly breakdown an amino acid called phenylalanine.

Babies with this disease have a missing enzyme called phenylalanine hydroxylase, which is needed to break down an essential amino acid phenylalanine into tyrosine in liver. This phenylalanine is accumulated and gets converted into phenyl pyruvic acid and other derivatives leading to mental retardation.

Type # 2. Chromosomal Disorders:

These are caused by the absence or excess or abnormal arrangement of one more chromosomes.

The examples are given below

It was described by J Langdon Down in 1866. It occurs due to the additional copy of chromosome number 21 or trisomy of chromosome 21 in humans and also seen in chimpanzees and other related primates.

i. Individuals are short statured with small, round head and furrowed tongue.

ii. Partially open mouth, palm is broad with characteristic palm crease.

iii. Slow mental development.

Klinefelter’s Syndrome:

It occurs due to the presence of an additional copy of X-chromosome resulting in the karyotype 45 + XXY which results into 47 chromosomes.

i. Individuals have masculine development but feminine characters like development of breasts, (gynaecomastia) etc.

ii. Poor bread growth and often sterile and feminine pitched voice.

Turner’s Syndrome:

i. It is a disorder caused due to the absence of one of the X-chromosome, i.e., 45 with XO.

i. Affected females are sterile as ovaries are rudimentary.

ii. Lack of secondary sexual characters and poor breasts development. Short stature, small uterus, puffy fingers and webbed neck.

iii. The chromosomal disorders can be studied by the analysis of karyotypes.


The propositus presented normal red blood cell (RBC) indices (5.37 10 9 /L) and Hb levels (14.1 g/dL) and microcytosis (MCV = 78.3fL) with hypochromia (MCH = 26.3 pg) without iron deficiency (RDW = 13.5%) and normal reticulocytes (1%). HbA2 (2.6%) and HbF (0.2%) levels were within the normal ranges. Peripheral blood smear did not show significant morphological changes. Physical examination was normal, without hepatomegaly or splenomegaly. Total bilirubin, haptoglobin, and LDH were all normal (

The inheritance of alpha-thalassemia is complex because the condition involves two genes : HBA1 and HBA2. People have two copies of the HBA1 gene and two copies of the HBA2 gene in each cell . Each copy is called an allele . Therefore, there are 4 alleles that produce alpha-globin, the protein that results from these genes. For each of the 2 genes, one allele is inherited from a person's father, and the other is inherited from a person's mother - so each person inherits 2 alleles from each parent. The different types of alpha-thalassemia result from the loss of some or all of these alleles.

If both parents are missing at least one alpha-globin allele, each of their children are at risk of having Hb Bart syndrome or hydrops fetalis, hemoglobin H (HbH) disease, or alpha-thalassemia trait . The precise risk depends on how many alleles are missing and which combination of the HBA1 and HBA2 genes is affected. [1]

  • a person with 1 mutated allele is a carrier and has no signs or symptoms
  • a person with 2 mutated alleles may have mild signs or symptoms of alpha-thalassemia (called alpha-thalassemia minor, or alpha-thalassemia trait)
  • a person with 3 mutated alleles has moderate to severe symptoms (called HbH disease)

When there are 4 mutated alleles, the condition is called alpha-thalassemia major or hydrops fetalis. In these cases, an affected fetus usually does not survive to birth, or an affected newborn does not survive long after birth. [3]


We have studied 145 subjects with borderline HbA2, defined as HbA2 values between 3.3% and 4.1%, and normal or slightly reduced MCV and MCH. Borderline HbA2 values have been confirmed in all subjects in 3 repeated determinations (twice in the same blood sample at first examination, the third in a second sample after 1-3 years). In these subjects, we had previously excluded the presence of mutations known to be associated with borderline HbA2, including HBB promoter mutations [−101 (HBB c.-151 C → T) −92 (HBB c.-142 C → T)], triplicated α-globin genes, and hemoglobin variants. 1 The aforementioned hemoglobin gene variants were excluded by appropriate methods (ie, HBB sequence from c.-720 to +137, HBA1 and HBA2 genotyping, and hemoglobin high performance liquid chromatography). We also sequenced the HBD gene, which was found normal from c.-580 to +70 in all but one subject (“DNA analysis”). Eighty normal subjects were used as controls.

The study has been approved by the University of Cagliari Institutional Review Board, and the patients signed the informed consent in accordance with the Declaration of Helsinki.

Venous peripheral blood was used for hematologic, hemoglobin, DNA, and expression studies

Complete whole blood cell count was obtained in all subjects, by electronic cell counters (Gen-S and LH750 Hematology Analyzer, Beckman Coulter). Types and amounts of hemoglobin were determined by high performance liquid chromatography (Bio-Rad Variant II analyzer, Bio-Rad). Two-level calibration of the instrument and sample analysis were carried out according to the manufacturer's recommendations. In some subjects, globin chain synthesis analysis was carried out as previously reported. 12

Genomic DNA was obtained with standard methods. The KLF1 gene was sequenced using previously described primers. 6 The common single nucleotide polymorphism C → T at position −158 of the HBG2 promoter (XmnI site rs7482144) was detected by direct digestion of polymerase chain reaction amplified DNA with XmnI restriction enzyme. 13 Genotyping of individual single nucleotide polymorphisms in the HBS1L-MYB (rs9399137) and BCL11A (rs 11886868) 14,15 loci was performed using TaqMan genotyping assay (Applied Biosystems).

The 2-step liquid erythroid cultures were obtained from peripheral blood with the procedure developed by Fibach et al. 16 Real-time RT-PCR quantification of mRNA expression was carried out using TaqMan RNA Assay kits according to the manufacturer's protocol (Applied Biosystems).

The amounts of mRNA relative to the endogenous 18S RNA were calculated on day 9 and day 11 of the second phase of liquid culture growth using the comparative cycle threshold (Ct) method (2 −ΔΔCt ). 17 The experiments were carried out in triplicate.

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As previously shown with microattribution, the existence of comprehensive data repositories allows comparative data analysis and reciprocally drawing conclusions that would have otherwise not been possible. HbVar data content was exploited in two such collaborative projects to study, from an evolutionary and functional perspective: (i) hemoglobin variants that may be due to the same mutation but lie on a different α-globin (HBA1 or HBA2) gene and (ii) hemoglobin variants and mutations leading to hereditary persistence of fetal hemoglobin that results from the same mutation but on either the HBG1 or HBG2 (fetal globin) gene.

In the first case, the study was performed within the context of the European Commission-funded ITHANET collaborative project (, in which we were able to identify 14 different hemoglobin variants resulting from identical mutations on either one of the two human α-globin (HBA1 or HBA2) paralogous genes ( 16). Also, in the second project, we managed to identify 11 different hemoglobin variants resulting from identical mutations on either one of the two human γ-globin paralogous genes, while seven other promoter variants either result in non-deletional hereditary persistence of fetal hemoglobin or are benign polymorphisms ( 17).

(SNPs/Variants according to the 1 NCBI SNP Database, 2 Ensembl, 3 PupaSUITE, and 4 UniProtKB, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
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HapMap Linkage Disequilibrium report for HBA2 (222846 - 223709 bp)

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