Anhaptoglobinemia

A number sign (#) is used with this entry because anhaptoglobinemia and hypohaptoglobinemia are caused by homozygous mutation in the gene encoding haptoglobin (HP; 140100) on chromosome 16q22.

Description

Anhaptoglobinemia refers to absence of the serum glycoprotein haptoglobin, a hemoglobin-binding acute-phase protein (summary by Teye et al., 2004). Serum levels of haptoglobin vary among normal persons: levels are low in the neonatal period and in the elderly, differ by population, and can be influenced by environmental factors, such as infection. Secondary hypohaptoglobinemia can occur as a consequence of hemolysis, during which haptoglobin binds to free hemoglobin (summary by Delanghe et al., 1998).

Clinical Features

Koda et al. (2000) reported 2 Asian anhaptoglobinemic patients with antihaptoglobin antibodies who developed anaphylactic transfusion reactions.

Teye et al. (2004) stated that anhaptoglobinemia has important clinical consequences, such as protecting against the cattle pathogen Trypanosoma brucei and being associated with higher CD4 cell counts in patients with HIV infection (Quaye et al., 2000).

Acquired Hypo- or Anhaptoglobinemia

Teye et al. (2003) noted that serum levels of haptoglobin can decrease secondarily following hemolysis, as haptoglobin is saturated by free hemoglobin. This is often observed in sub-Saharan African regions where malaria is endemic. In those with low haptoglobin levels at baseline, hemolysis due to malaria can result in clinical anhaptoglobinemia.

Other Features

Panter et al. (1985) found an association between familial idiopathic epilepsy and low serum levels of haptoglobin. Artificially-induced hypohaptoglobinemia in mice caused delayed clearance of free hemoglobin from the central nervous system and engendered the peroxidation of brain lipids. Panter et al. (1985) hypothesized that hypohaptoglobinemia, either inherited or acquired via traumatic processes, may prevent efficient clearance of interstitial hemoglobin from the central nervous system, thereby predisposing these individuals to encephalic inflammation and the appearance of seizure disorders.

Molecular Genetics

In a Japanese individual with anhaptoglobinemia found by ELISA analysis of 9,711 unrelated blood samples, Koda et al. (1998) identified a homozygous 28-kb deletion allele on chromosome 16q22 (140100.0003) extending from the promoter region of the HP gene to exon 5 of the haptoglobin-related gene (HPR; 140210), resulting in a null allele, termed HP0.

Teye et al. (2003) found that 17 (13.8%) of 123 Ghanaian individuals with undetectable malaria infection had decreased serum haptoglobin as assessed by double immunodiffusion followed by Western blotting. Nine (7.3%) were anhaptoglobinemic and 8 (6.5%) were hypohaptoglobinemic. There was a strong association between a -61A-C polymorphism in the HP gene (140100.0004) and anhaptoglobinemia (p = 0.0125).

Teye et al. (2004) identified a heterozygous mutation in the HP gene (I247T; 140100.0005) in a Ghanaian individual who was anhaptoglobinemic as assessed by several assays. The I247T mutation caused reduced expression of the HP protein when transfected into COS-7 cells. This individual was also homozygous for the hypomorphic -61A-C allele (140100.0004).

Hypohaptoglobinemia

Koda et al. (1998) found that 7 Japanese persons from 3 families with hypohaptoglobinemia carried the deletion allele HP0 (140100.0003) in compound heterozygosity with 1 of the codominant HP polymorphisms. Six individuals with the HP2 (140100.0002)/HP0 genotype had an extremely low level of haptoglobin compared to controls with the HP2/HP2 genotype, whereas 1 individual with the HP1 (140100.0001)/HP0 genotype had a serum level that was approximately half the level of controls with the HP1/HP1 genotype. This demonstrated a gene dosage effect.

Population Genetics

Koda et al. (2000) estimated that the frequency of individuals homozygous for the Asian deletion HP0 allele (140100.0003) was 1 in 4,000 among Japanese, 1 in 1,500 among Koreans, and 1 in 1,000 among Chinese. This allele had not been identified in non-Asian populations.