The nematode CED-4 protein and its human homolog Apaf-1 play a central role in apoptosis by functioning as direct activators of death-inducing caspases. A novel human CED-4/Apaf-1 family member called CARD4 was identified that has a domain structure strikingly similar to the cytoplasmic, receptor-like proteins that mediate disease resistance in plants. CARD4 interacted with the serine-threonine kinase RICK and potently induced NF-B activity through TRAF-6 and NIK signaling molecules. In addition, coexpression of CARD4 augmented caspase-9-induced apoptosis. Thus, CARD4 coordinates downstream NF-B and apoptotic signaling pathways and may be a component of the host innate immune response.

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Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF-la) located on chromosome 12q. We have identified four novel HNF-la missense mutations in M0DY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in M0DY3. We observed no HNFla mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes. Diabetes 46:1081-1086,1997MODY. The MODY1 locus, on chromosome 20q, was shown to be linked in a single extended family (2). M0DY1 was recently shown to be caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF4a) (3). MODY2, located on chromosome 7p (4), is caused by mutations in the glucokinase gene (5). MODY3 was mapped to chromosome 12q (6) and is known to be caused by mutations in another transcription factor, HNF-la (7). Although the relative prevalence of these MODY subtypes varies regionally (8-10), families linked to chromosome 12q are the most frequently described. The glucokinase defects in MODY2 interfere with glucose uptake, resulting in hyperglycemia (5). Although the mechanism of hyperglycemia in MODY1 and MODY3 is not yet understood, phenotypic characterization of these families has shown a deficient insulin secretion response to glucose (11-13).We report here the characterization of the MODY3 gene M region and the results of mutation analysis in eight different aturity-onset diabetes of the young (MODY) is a MODY3 families. We show that MODY3 can be caused by a form of NIDDM with a strong genetic basis, number of different mutations in HNF-la including a mutaDiagnostic criteria for MODY include 1) age of tional hotspot. onset <25 years, 2) correction of fasting hyperglycemia without insulin for at least 2 years, 3) nonketotic RESEARCH DESIGN AND METHODS disease, and 4) autOSOmal dominant mode Of inheritance (1). Family ascertainment and linkage analysis. Families were ascertained based It is therefore expected that a Significant proportion Of MODY on the criteria described by Lehto et al. (13). Genomic DNA was isolated from is caused by Single-gene defects. To date, linkage analysis has P eri P heral blood lymphocytes using standard protocols. Genotyping was pershown that three different, dominant-acting loci can cause fo ™ ed t^^ flu0