title: Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease.
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 (homozygousANKZF1R585Q mutation and compound heterozygousANKZF1E152K and V32_Q87del mutations, respectively) and two patients with one mutatedANKZF1allele. 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. TheANKZF1mutations identified in IO IBD patients with two mutatedANKZF1alleles 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 homozygousANKZF1R585Q 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 inANKZF1result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD.
authors.affiliation: From the Division of Pediatrics, Wilhelmina Children's Hospital.|the Regenerative Medicine Center and Center for Molecular Medicine, and.
authors.forename: Désirée Y
authors.initials: DY
authors.lastname: van Haaften-Visser
authors.affiliation: the Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.affiliation: the Regenerative Medicine Center and Center for Molecular Medicine, and.
authors.forename: Enric
authors.initials: E
authors.lastname: Mocholi
authors.affiliation: From the Division of Pediatrics, Wilhelmina Children's Hospital.
authors.forename: Joris M
authors.initials: JM
authors.lastname: van Montfrans
authors.affiliation: the Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|the SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and.
authors.forename: Abdul
authors.initials: A
authors.lastname: Elkadri
authors.affiliation: the Regenerative Medicine Center and Center for Molecular Medicine, and.
authors.forename: Ester
authors.initials: E
authors.lastname: Rieter
authors.affiliation: the Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|the SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and.
authors.forename: Karoline
authors.initials: K
authors.lastname: Fiedler
authors.affiliation: From the Division of Pediatrics, Wilhelmina Children's Hospital.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.affiliation: the Regenerative Medicine Center and Center for Molecular Medicine, and.
authors.forename: Emily M M
authors.initials: EMM
authors.lastname: Triffaux
authors.affiliation: the Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.affiliation: the Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: the Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.affiliation: From the Division of Pediatrics, Wilhelmina Children's Hospital.
authors.forename: Edward E S
authors.initials: EES
authors.lastname: Nieuwenhuis
authors.affiliation: the Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|the SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: the Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: From the Division of Pediatrics, Wilhelmina Children's Hospital.
authors.forename: Roderick H J
authors.initials: RHJ
authors.lastname: Houwen
authors.affiliation: From the Division of Pediatrics, Wilhelmina Children's Hospital, p.j.coffer@umcutrecht.nl.|the Regenerative Medicine Center and Center for Molecular Medicine, and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
mesh_terms: D017668:Age of Onset; D000483:Alleles; D017089:Ankyrin Repeat / Q000235:genetics*; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015894:Genome, Human; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007223:Infant; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015032:Zinc / Q000737:chemistry; D016335:Zinc Fingers
chemical_list: C000621130:ANKZF1 protein, human; D002352:Carrier Proteins; D034741:RNA, Small Interfering; D015032:Zinc
keywords: ANKZF1; apoptosis; cell biology; human genetics; infantile-onset inflammatory bowel disease; inflammatory bowel disease (IBD); mitochondria; mitochondrial stress; whole-exome sequencing