Mice homozygous for the spontaneous mutation curvy tail (curt) were initially described by the deviant phenotypes of an S-shaped tail, crooked digits, small body size, "squinty" eyes and hearing loss. In heterozygote crosses, the number of homozygous progeny born (17%) does not reach the expected Mendelian ratio with nearly 4% of homozygotes stillborn. Surviving homozygotes die by 3 months of age. This mutation was subsequently defined as a 4 base pair deletion in Clec16a exon 21, which results in a frameshift mutation, introduction of novel amino acids, and an early termination codon, with a significant decrease in transcript levels detected. CLEC16A normally has a high level of expression in a broad array of immune cells, particularly B cells, NK cells, and T cells, and in Purkinje cells, neurons of the deep cerebellar nuclei, and activated astrocytes, and has been associated with an array of autoimmune disorders including type 1 diabetes, multiple sclerosis, and adrenal dysfunction in human. CLEC16A is an endosomal protein essential for proper autolysosomal clearance and Redmann et al. found dispersion of the Golgi in cultured cells from Clec16a homozygous null mice. CLEC16A has E3 ubiquitin ligase activity that ubiquitinates NRDP1 and forms a CLEC16A-NRDP1-USP8 mitophagy regulating complex in pancreatic Beta cells (Soleimanpour et al). Disruption of Clec16a has been shown to block diabetes onset in the NOD background (Schuster et al.). Homozygotes for either curt or a targeted null allele have been shown to have a loss of Pukinje cells that is histologically evident by 8 weeks of age. Thus, this mutant provides a model for studies in autophagy, mitophagy, and related signal transduction in an array of diseases.
