Abstract
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 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32_Q87del mutations, respectively) and two patients with one mutated ANKZF1 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 ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 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 ANKZF1 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 ANKZF1 result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD.
Highlights
Infantile-onset inflammatory bowel disease (IO Inflammatory bowel disease (IBD)) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important
Using a combination of homozygosity mapping and whole-exome sequencing, we identified a homozygous mutation in the ankyrin repeat and zinc-finger domain-containing 1 (ANKZF1) gene in one Infantile-onset inflammatory bowel disease (IO IBD) patient
The clinical phenotype resembled the phenotype of patients with IL10 deficiency, no mutations were found in IL10, IL10RA, and IL10RB, as well as in several other genes known to be associated with IBD (including RAG1, RAG2, DOCK8, and chronic granulomatous disease (CGD)-related genes)
Summary
Mutation of ANKZF1 in four patients with infantile-onset inflammatory bowel disease. The female index patient presented at the age of 6 weeks with loose stools containing blood and mucus as well as severe ulcerative skin lesions at the perioral and perianal regions and extremities (Fig. 1, A and B). One boy carried compound heterozygous ANKZF1 mutations: g.220096885GϾA, resulting in skipping of half of exon 2 and exon 3 (p.V32_Q87del), and g.220097301GϾA (c.454GϾA, p.E152K) (Fig. 1, E and F) This patient presented in the first 6 months of life with a pancolitis. In EBV-transformed B-lymphocytes from the patient with the compound heterozygous ANKZF1 V32_Q87del and E152K mutations, ANKZF1 mRNA and protein expression were equal to the ANKZF1 levels in control cells (Fig. 2D). To test whether the decline in protein expression in the patient with a homozygous ANKZF1 R585Q mutation may be due to an increased proteasomal degradation of ANKZF1, fibroblasts and EBV-transformed B-lymphocytes were left untreated or treated with the proteasome inhibitor MG132, and ANKZF1 protein levels were analyzed.
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