Blood Group, Junior System

A number sign (#) is used with this entry because the Junior(a-) blood group phenotype is caused by homozygous or compound heterozygous mutation in the ABCG2 gene (603756) on chromosome 4q22.

Description

Individuals with Jr(a-) blood group lack the Jr(a) antigen on their red blood cells. These individuals may have anti-Jr(a) antibodies in their serum, which can cause transfusion reactions or hemolytic disease of the fetus or newborn. Although the clinical significance of the Jr(a-) blood group has been controversial, severe fatal hemolytic disease of the newborn has been reported. The Jr(a-) phenotype has a higher frequency in individuals of Asian descent, compared to those of European descent (summary by Kim et al., 2010 and Zelinski et al., 2012).

Clinical Features

Nakajima and Ito (1978) reported a 30-year-old Japanese woman with no history of blood transfusion whose child developed hemolytic disease of the newborn. The infant became jaundiced within 3 days of birth, and blood showed a strongly positive direct antiglobulin reaction. The maternal serum was found to contain anti-Jr(a) IgG antibodies. Red cells of the baby and the father carried the Jr(a) antigen, whereas those of the mother did not. The mother had a previous history of spontaneous abortion at 3 months' gestation.

Peyrard et al. (2008) reported fatal hemolytic disease of the fetus and newborn associated with anti-Jr(a) antibodies. Prenatal ultrasound of a 28-year-old Caucasian woman of Gypsy Spanish origin at 29 weeks' gestation pregnancy showed fetal cardiomegaly and hepatomegaly. She had a history of 2 abortions and 1 full-term pregnancy, as well as a history of massive transfusion with Jr(a)-positive blood. In this pregnancy, an emergency cesarean section was performed at 36 weeks' gestation; the newborn was hydropic with severe anemia and died 30 hours after birth. The mother was found to have the Jr(a-) phenotype with anti-Jr(a) antibodies. Peyrard et al. (2008) stated that this was the first documented case of fatal hemolytic disease of the fetus or newborn due to anti-Jr(a), which provided new information about the clinical significance of anti-Jr(a).

Kim et al. (2010) reported a 33-year-old nulliparous Korean woman with no history of transfusion who had the Jr(a-) red blood cell phenotype and anti-Jr(a) IgG antibodies. She delivered male twins with the Jr(a) phenotype, and circulating maternal Jr(a) antibodies were detected in the babies' serum. The twins had mild hemolytic disease of the newborn, which was successfully treated with phototherapy; they had no further complications.

Inheritance

The Jr(a-) phenotype is inherited as an autosomal recessive trait (Zelinski et al., 2012).

Diagnosis

Miyazaki et al. (1994) developed a human monoclonal IgG3 antibody against the Jr(a) antigen using EBV-transformed lymphocytes derived from a Japanese woman with serum anti-Jr(a) antibodies hybridized with a mouse myeloma cell line. Studies on a panel of red cells demonstrated the specificity of the antibody for the Jr(a) antigen. Screening of 28,744 Japanese blood donor samples using the antibody detected 19 (0.07%) agglutination-negative samples, which were confirmed as Jr(a-) by conventional anti-Jr(a) antisera.

Molecular Genetics

By SNP haplotype analysis of 4 probands with Jr(a) antibodies to red blood cells, indicating that their red blood cells were of the Jr(a-) phenotype, Zelinski et al. (2012) identified a shared homozygous region on chromosome 4q22 including the ABCG2 gene. Analysis of coding exons identified 4 different mutations in the ABCG2 gene (603756.0001-603756.0004) in the homozygous or compound heterozygous state. Three of the mutations caused null alleles, and erythrocytes from all individuals did not display the Jr antigen. One woman and her blood-group compatible sister were Caucasian, another woman and her blood-group compatible brother were Asian, and 2 further unrelated individuals were Asian. The findings indicated that the Jr(a-) blood group phenotype is defined by ABCG2 null alleles.

In 18 unrelated women with the Jr(a-) blood type, Saison et al. (2012) identified 8 different null mutations in the ABCG2 gene (see, e.g., 603756.0004-603756.0006). All mutations occurred in the homozygous or compound heterozygous state, indicating autosomal recessive inheritance. All women were identified during pregnancy after having developed anti-Jr(a) antibodies. Protein blot and flow cytometric analysis confirmed absence of the ABCG2 transporter on red blood cells of Jr(a-) individuals. Six women belonging to Gypsy communities of southwestern Europe were homozygous for the same mutation (R236X; 603756.0004), consistent with a founder effect. Because of the possible role of the ABCG2 protein as a uric acid transporter, Saison et al. (2012) measured plasma samples from pregnant Jr(a-) women, but urate levels were not significantly increased compared to controls. However, plasma porphyrin was significantly decreased and red blood cell porphyrin significantly increased in pregnant Jr(a-) women, suggesting a role for ABCG2 in exporting excess porphyrin from red blood cells. These individuals showed no symptoms of porphyria, but the aberrations in porphyrin transport may place them at risk under certain conditions. The mutation was found after identifying the orthologous protein on cat erythrocytes.

Population Genetics

Nakajima and Ito (1978) determined that the frequency of the Jr(a-) phenotype is about 0.026% in Japan.

Miyazaki et al. (1994) found that the frequency of the Jr(a-) phenotype was 0.07% in Japan.

Zelinski et al. (2012) noted that the Jr(a-) phenotype is rare in European and North Americans of European descent, but is more common in Japan, where the incidence has been reported to range from a high of 1 in 60 in the Niigata area to a low of 1 in 3,800 in the Tokyo area.