title: Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene.
abstract: Steatorrhea and malabsorption of lipid-soluble vitamins due to exocrine pancreatic insufficiency are common in patients with cystic fibrosis and are predominant in Shwachman-Bodian-Diamond, Pearson, and Johanson-Blizzard syndromes. In four patients who suffered from congenital exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis, we excluded these disorders and identified, by using homozygosity mapping, a mutation in the COX4I2 gene. The COX4 protein is an essential structural subunit of cytochrome c oxidase complex and has two isoforms, encoded by two different genes. We show that the ratio of COX4I2 to COX4I1 mRNA is relatively high in human acinar cells. The mutation is associated with marked reduction of COX4I2 expression and with striking attenuation of the physiologic COX4I2 response to hypoxia. Mutation analysis of COX4I2 is warranted in patients with malabsorption due to exocrine pancreatic insufficiency and in patients with dyserythropoeitic anemia.
authors.affiliation: The Metabolic Disease Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Shteyer
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.forename: Fida' Aziz
authors.initials: FA
authors.lastname: Al-Hijawi
authors.forename: Rojette
authors.initials: R
authors.lastname: Kidess
authors.forename: Shoshanah
authors.initials: S
authors.lastname: Revel-Vilk
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D000595:Amino Acid Sequence; D000742:Anemia, Dyserythropoietic, Congenital / Q000235:genetics*; D045304:Cytochromes c / Q000235:genetics*; D003576:Electron Transport Complex IV; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics*; D005260:Female; D006801:Humans; D015576:Hyperostosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012886:Skull / Q000473:pathology*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D045304:Cytochromes c; C539675:COX4I2 protein, human; D003576:Electron Transport Complex IV