Familial hyperinsulinism (HI) is the most common cause of persistent neonatal hyperinsulinaemic hypoglycemia. Linkage analysis in 15 families (12 Ashkenazi Jewish, 2 consanguineous Arab, 1 non-Jewish Caucasian) mapped HI to chromosome 11p14-15.1 (lod score = 9.5, theta = 0 at D11S921). Recombinants localized the disease locus to the 6.6 cM interval between D11S926 and D11S928. In Jewish families, association (p = 0.003) with specific D11S921/D11S419 haplotypes suggested a founder effect. This locus, which is important for normal glucose-regulated insulin secretion, represents a candidate gene for studies of other diseases of beta-cell dysfunction including non-insulin-dependent diabetes mellitus (NIDDM).

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Four distinct human B-lymphoid cell lines possess the ability to circumvent the mechanism regulating intracellular transport of immunoglobulin protein. These cells do not produce light chains, yet they express ,u heavy chains on the cell surface at comparable levels to B-cell lines that produce native forms of both proteins. The IL-chain mRNA produced in all four cell lines was found to contain an identical deletion of most of the heavy-chain variable (VH) region (75% of the 3' portion), with no apparent alteration in constant (C) region structure. The truncated gL (Iu*)-chain mRNA in these cells was created through the use of a cryptic splice donor site found within the human VH gene(s) utilized by these B-cell lines. The truncated IL* chains exhibited a decreased ability to associate with the intracellular transport regulatory protein, heavychain binding protein (BiP). This result indicates that VH region structure, in addition to C,,1 region structure, influences the formation of the BiP recognition site on the heavy chain. Furthermore, it suggests that the mechanism allowing for cell-surface expression of the p* chains in the absence of light-chain pairing is the inability of BiP to bind to the IL* chains and hence prevent their intracellular transport. The high frequency with which the ,I-only surface immunoglobulin positive phenotype is present in our collection of human B-cell lines and the isolation of one of the cell lines from a healthy individual also suggest that B cells of this type may represent a significant subpopulation among the normal human B-cell repertoire.In the developmental pathway for mammalian B lymphocytes, the immunoglobulin heavy (H)-chain-only phenotype is normally limited to the precursor population known as pre-B cells, which generally synthesize the ,t form of H chain (1-3). Certain instances can arise though where more mature B-lymphoid cells can also stably express H chains in the absence of any light (L)-chain synthesis. The best documented examples of this phenomenon are found in plasma cell stage lines isolated from patients with 'y H-chain disease (4) or represented by certain variant clones isolated during culture of mouse plasmacytomas (5). The H chain produced by the plasmacytoid cell lines from each of these sources is always found to be structurally altered from the native H-chain protein of the same isotype and is generally secreted by the cell as an H-chain-only multimeric complex. The ability of these altered H chain (H*) to be transported intracellularly in the absence of L-chain association contrasts with the block in intracellular transport for native ,4 chains in pre-B cells (2).An explanation to this anomaly has been recently provided by studies showing that H-chain transport in B-lymphoid cells is regulated by an endoplasmic reticulum (ER)-localized protein termed H-chain binding protein (BiP; see ref. 6), which apparently belongs to the glucose-regulated family of proteins (7). BiP appears to regulate transport of several membrane and secreted glycopr...

The sporozoite form of Plasmodium falciparum displays on its surface the circumsporozoite (CS) protein. The central domain of this protein possesses a reiterated tetrapeptide sequence Asn-Ala-Asn-Pro (NANP), and greater than 90% of the sporozoite-specific antibodies obtained from individuals living in malaria endemic areas recognize epitopes within this repeat sequence. Considering the highly repetitive structure of this naturally occurring antigen and its immunodominance, we were interested in analyzing the structural diversity of antibodies that bind to the (NANP)3 sequence. Molecular characterization of immunoglobulin heavy and light chain mRNA was performed for five hybridomas that produce antibodies with binding specificity for the dodecapeptide (NANP)3. These hybridomas were produced in BALB/c mice by inoculation with whole P. falciparum sporozoites. Sequence analysis and Northern blotting showed that for heavy chain, three hybridomas used VH elements that belong to the VHIX family and two to the VHJ558 family. Four different V kappa subgroups were represented among the light chains. Different D and J kappa segments are also utilized, while four heavy chain gene rearrangements involved the JH4 segment. These results indicated that multiple VH-VL gene combinations can code for reactivity to the (NANP)3 sequence, demonstrating that the murine antibody response to this immunodominant region is structurally heterogeneous.