A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-κB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.).

The high-incidence erythrocyte blood group antigen Jr(a) has been known in transfusion medicine for over 40 years. To identify the gene encoding Jr(a), we performed SNP analysis of genomic DNA from six Jr(a-) individuals. All individuals shared a homozygous region of 397,000 bp at chromosome 4q22.1 that contained the gene ABCG2, and DNA sequence analysis showed that ABCG2 null alleles define the Jr(a-) phenotype.

Bowen-Conradi syndrome (BCS) is an autosomal-recessive disorder characterized by severely impaired prenatal and postnatal growth, profound psychomotor retardation, and death in early childhood. Nearly all reported BCS cases have been among Hutterites, with an estimated birth prevalence of 1/355. We previously localized the BCS gene to a 1.9 Mbp interval on human chromosome 12p13.3. The 59 genes in this interval were ranked as candidates for BCS, and 35 of these, including all of the best candidates, were sequenced. We identified variant NM_006331.6:c.400A-->G, p.D86G in the 18S ribosome assembly protein EMG1 as the probable cause of BCS. This mutation segregated with disease, was not found in 414 non-Hutterite alleles, and altered a highly conserved aspartic acid (D) residue. A structural model of human EMG1 suggested that the D86 residue formed a salt bridge with arginine 84 that would be disrupted by the glycine (G) substitution. EMG1 mRNA was detected in all human adult and fetal tissues tested. In BCS patient fibroblasts, EMG1 mRNA levels did not differ from those of normal cells, but EMG1 protein was dramatically reduced in comparison to that of normal controls. In mammalian cells, overexpression of EMG1 harboring the D86G mutation decreased the level of soluble EMG1 protein, and in yeast two-hybrid analysis, the D86G substitution increased interaction between EMG1 subunits. These findings suggested that the D-to-G mutation caused aggregation of EMG1, thereby reducing the level of the protein and causing BCS.

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