Chromosome Information and Courses from MediaLab, Inc.

Thalassemias are named according to the affected gene or globin chain which is showing reduced or absent synthesis. Globin chain loci are found on chromosome 11 (Beta, Delta, Epsilon, and Gamma) chromosome 16 (Alpha, and Zeta)

Deletion of two out of four alpha chain loci results in alpha thalassemia minor. The deletions may be homozygous (two on the same chromosome) or heterozygous (one from each of two chromosomes). Alpha thalassemia minor does not produce a clinical disease but may be discovered upon routine testing. Both the homozygous and heterozygous form are common in Southeast Asians. The homozygous form is also seen in American Blacks.

In the Silent Carrier (-/), only one loci is deleted or inactive. Hemoglobin A is still able to be made to its fullest amount, 97-98%.(drawing modified from Harmening, 1999)

When three loci of alpha chains are deleted (--/-) or inactive, only 70-90% of Hemoglobin A is made. The excess beta chains that remain unpaired form the tetramers of Hemoglobin H.(drawing modified from Harmening, 1999)

Thalassemias are part of a group of hemoglobin synthesis disorders in which a defect exists in the rate of production of one or more of the globin chains. This defect results from either a heterozygous or homozygous deletion or inactivation of a globin chain gene.Thalassemias are named according to the affected gene or the globin chain that is showing reduced or absent synthesis.Globin chain loci are found on: chromosome 11 (beta, delta, epsilon, and gamma) chromosome 16 (alpha, and zeta)

Heterozygous states can express themselves as beta thalassemia minor, beta thalassemia intermedia, and silent carrier. The homozygous state is beta thalassemia major, though one type of beta thalassemia intermedia is caused by a homozygous state. A larger deletion on chromosome 11 results in delta-beta thalassemia, which also has heterozygous and homozygous states.

Beta thalassemia major, B0/B0 (two gene mutations, deletions or combination) results in very few to no beta chains being produced.Hemoglobin A levels are at or near 0%.(drawing modified from Harmening, 1999)

Beta chain synthesis is controlled by two gene loci; one on each of chromosome 11. Chromosome 11 also carries the gene loci for delta chains, G-gamma and A-gamma chains and embryonic epsilon chains. Normal chromosome 11 is depicted in the image below. In the genotypic notation of beta thalassemia, a "+" represents a reduction in beta chain production whereas a "0" represents a complete deletion of a locus. The "+s" represents a silent carrier. Delta chain deletions may be present in combination with beta chain deletions.(drawing modified from Harmening, 1999)

In Beta thalassemia minor, B0/B, one beta gene locus is completely deleted or inactive.Hemoglobin A production is down to 70% - 85% in this state of beta thalassemia.(drawing modified from Harmening, 1999)

In Beta thalassemia intermedia, B+s/B+s, both beta chain loci show a partial deletion or inactivation of the gene.Hemoglobin A is made to only 55% to 75% of its normal amount.(drawing modified from Harmening, 1999)

Delta-beta thalassemia intermedia exists when both gene loci for beta and delta chains are deleted or inactive on one chromosome, while the other chromosome contains a beta chain gene that is partially deleted or inactive. Delta-Beta 0/ Beta+sIn this state the majority of hemoglobin will be Hb F, with very little Hb A and A2 present.(drawing modified from Harmening, 1999)

A gene is a hereditary unit or sequence of the nucleotide bases ACGT, occupying a fixed location or locus on the chromosome. It is these genes that carry all the information for life processes.DNA is rewritten into 3 types of RNA, each with a specific task: Messenger RNA (mRNA)carries the protein message to the cytoplasm. Ribosomal RNA (rRNA) is the location of protein synthesis. Transfer RNA (tRNA) is responsible for amino acid transport.Each 3-base nucleotide sequence (codon) codes for a specific amino acid. Some amino acids have more than one codon to direct their placement; this is termed degeneracy.

A hemochromatosis gene, HFE, was identified in 1996. Mutations in the HFE gene are found in the majority of patients diagnosed with hereditary hemochromatosis (HH). The locus for the gene is on the long arm of chromosome 6 where it codes for a membrane protein, HFE. The exact mechanism of the role of HFE protein in iron metabolism is incompletely understood. It is thought that HFE, along with a second protein, beta-2 microglobin, interacts with transferrin receptors (TfR) on cell membranes. This interaction supresses the affinity of transferrin for TfR, thus lowering the uptake of transferrin--and its attached iron--into the cell. Transferrin receptors have been found on the surface of a variety of cells, with the greatest concentration on cell membranes of intestinal cells, hepatocytes, and RBC precursors. In addition to HFE, HH is also associated with mutations in other genes involved in iron homeostasis, including hemojuvelin (HJV), TfR, hepcidin, and ferroportin. Hepcidin production is reduced in HH due to all of these genetic causes, with a resulting increase in iron absorption. Mutations in HFE are the most common cause of HH.

Three separate loci (ABO, Hh, and Se) contain the genes that control the location and occurrence of the A and B antigens. Hh and Se genes are closely linked on chromosome 19. The precursor substance is acted upon by the H gene and is converted to H substance. The product of the H gene is an enzyme fucosyltransferase, responsible for attaching fucose to the terminal galactose of the precursor substance on the RBC membrane and thus forming H substance. There are only two recognized alleles at this locus: the active form, H, and an amorph, h. The H gene is a high-incidence gene. People who inherit hh are extremely rare. Since the h gene is amorphic, it does not act on the precursor substance.

Specialists in cytogenetics detect chromosome abnormalities and genetic disorders. Cytogenetics counseling may only be performed by an individual licenses in the cytogenetics specialty at the director level. Specialists in molecular genetics analyze DNA and RNA to find disease-related genotypes, mutations, and phenotypes in order to detect or predict disease and identify carriers. Specialists in histocompatibility test to determine tissue compatibility, prevent infections, and investigate and post-transplant problems. Techniques include blood typing, HLA typing, HLA antibody screening, disease markers, flow cytometry, crossmatching, HLA antibody identification, lymphocyte immunophenotyping, immunosuppressive drug assays, allogenic, isogeneic and autologous bone marrow processing and storage, mixed lymphocyte culture, stem cell culture, cell mediated assays, and assays for the presence of cytokines. Specialists in andrology and embryology examine gametes and embryos, including production, morphology, number, and motility, to address issues of fertility and infertility.

A Barr body appears as a small drumstick-like projection on one of the lobes of a some of the neutrophil in females. Barr bodies are attached to the nuclear lobe by a single narrow stalk which distinguishes them from other thicker projections, sometimes referred to as "clubs." Clubs have a thicker, and sometimes, a double stalk. This projection can be seen in both males and females and has no clinical significance. Barr bodies must also be distinguished from hair-like projections sometimes seen in the band form, following irradiation or in patients with a malignant tumor that has metastasized. Since Barr bodies are the morphological expression of the inactivated X chromosome, one Barr body can be seen in up to 3% of the neutrophils on a female's peripheral blood slide. In rare chromosome disorders in which three or more X chromosomes are present, two to three Barr bodies per neutrophil can be seen. Recognition of a Barr body in a neutrophil is important in order to avoid reporting it as abnormal unless two or more per neutrophil are seen.