tRNA endonuclease ANKZF1
cytoplasm
Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease.
Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 (<i>ANKZF1</i>) alleles (homozygous <i>ANKZF1</i> R585Q mutation and compound heterozygous <i>ANKZF1</i> E152K and V32_Q87del mutations, respectively) and two patients with one mutated <i>ANKZF1</i> allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The <i>ANKZF1</i> mutations identified in IO IBD patients with two mutated <i>ANKZF1</i> alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous <i>ANKZF1</i> R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in <i>ANKZF1</i> result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD.