M. Alexandra Glucksmann

Human CARD4 Protein Is a Novel CED-4/Apaf-1 Cell Death Family Member That Activates NF-κB

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-κB activity through TRAF-6 and NIK signaling molecules. In addition, coexpression of CARD4 augmented caspase-9-induced apoptosis. Thus, CARD4 coordinates downstream NF-κB and apoptotic signaling pathways and may be a component of the host innate immune response.

A Novel Nervous System β Subunit that Downregulates Human Large Conductance Calcium-Dependent Potassium Channels

The pore-forming α subunits of many ion channels are associated with auxiliary subunits that influence channel expression, targeting, and function. Several different auxiliary (β) subunits for large conductance calcium-dependent potassium channels of the Slowpoke family have been reported, but none of these β subunits is expressed extensively in the nervous system. We describe here the cloning and functional characterization of a novel Slowpoke β4 auxiliary subunit in human and mouse, which exhibits only limited sequence homology with other β subunits. This β4 subunit coimmunoprecipitates with human and mouse Slowpoke. β4 is expressed highly in human and monkey brain in a pattern that overlaps strikingly with Slowpoke α subunit, but in contrast to other Slowpoke β subunits, it is expressed little (if at all) outside the nervous system. Also in contrast to other β subunits, β4 downregulates Slowpoke channel activity by shifting its activation range to more depolarized voltages and slowing its activation kinetics. β4 may be important for the critical roles played by Slowpoke channels in the regulation of neuronal excitability and neurotransmitter release.

Novel mutations and a mutational hotspot in the MODY3 gene

Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1a (HNF-1α) located on chromosome 12q. We have identified four novel HNF-1α 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 HNF-1α 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.