The activation-induced cytidine deaminase (AID) gene, specifically expressed in germinal center B cells in mice, is a member of the cytidine deaminase family. We herein report mutations in the human counterpart of AID in patients with the autosomal recessive form of hyper-IgM syndrome (HIGM2). Three major abnormalities characterize AID deficiency: (1) the absence of immunoglobulin class switch recombination, (2) the lack of immunoglobulin somatic hypermutations, and (3) lymph node hyperplasia caused by the presence of giant germinal centers. The phenotype observed in HIGM2 patients (and in AID-/- mice) demonstrates the absolute requirement for AID in several crucial steps of B cell terminal differentiation necessary for efficient antibody responses.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-linked FHL. Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation.

Due to a cloning error, the sequence reported for ING1 was incorrect. The error appears to have been a result of a compression introducing a frameshift and of the ING1 gene encoding several differentially spliced isoforms that contain a common 3′ exon, one of which is of a size very similar to that reported in the publication above. The original (ING1a´, previously called ING1) and the corrected (ING1a) sequences of the isoform of ING1 that was first reported are shown at right (a). The sequence that we reported was frameshifted and truncated at the 5′ end, and we now know that it encodes a protein with a predicted mass of 46,751 rather than the predicted 33,253 daltons. A truncated ING1a message also encodes an expressed protein of 23,656 daltons that results from initiation at the first internal ATG in the conserved exon. An alternatively spliced isoform, ING1b, shares a common 3′ exon with ING1a and encodes a protein with a predicted mass of 31,843 daltons. We now refer to the proteins encoded by this gene as p47 ING1a , p33 ING1b and p24 ING1c due to their relative electrophoretic mobilities. These polypeptides are found in the majority of primary and established tissue culture cells examined, including those of fibroblast, epithelial and glial origin. A schematic diagram of the proteins encoded by the two major transcripts of ING1 are shown (b). All three proteins contain a region with a high degree of homology to PHD fingers that are implicated in transcriptional regulation. The complete, corrected nucleotide sequences for the cDNAs encoding ING1a and-b are available at accession numbers AF181849 (for ING1a, formerly listed as AF001954) and AF181850 at GenBank. We regret any inconvenience that may have resulted from the sequencing error. Expression constructs encoding full-length ING1a, ING1b and ING1c proteins are available from Dongping Ma,

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder characterized by the early onset of overwhelming activation of T lymphocytes and macrophages, invariably leading to death, in the absence of allogeneic bone marrow transplantation. Using genomewide genetic linkage analysis, we analyzed a group of 17 families with FHL and mapped a locus for FHL to the proximal region of the long arm of chromosome 10. Ten families showed no recombination with three tightly linked markers, D10S1650 (LOD score [Z]=6.99), D10S556 (Z=5.40), and D10S206 (Z=3.24), with a maximum multipoint LOD score of 11.22 at the D10S1650 locus. Haplotype analysis of these 10 families allowed us to establish D10S206 and D10S1665 as the telomeric and the centromeric flanking markers, respectively. Heterogeneity analysis and haplotype inspection of the remaining families confirmed that in seven families FHL was not linked to the 10q21-22 region, thus providing evidence for genetic heterogeneity of this condition.