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.

Figure 1

Pedigrees of Families A and B and the Haplotypes along the Critical Region on Chromosome 20 Patients' symbols are filled. Numbered symbols represent individuals whose DNA samples were available for analysis. The polymorphic microsatellite markers and their chromosomal locations (in Mb) are given in the upper left panel. C20-22.65M_TAT stands for hg18_chr20:22654664-22655109. C20-29.67M_CA stands for hg18_ chr20:29675861-29676305.

Figure 2

Skull and Abdominal Radiological Findings (A and B) Patient 1989's thickened calvarium: (A) Brain CT scan, axial view; (B) skull x-ray. (C and D) Abdominal CT scan of patients 1989 (C) and 3041 (D) disclosing pancreatic atrophy with massive fatty infiltration (arrows) and increased hepatic density (asterisk).

Figure 3

Bone marrow biopsy of patient 1989. Note multi-nucleated red cell precursors (solid arrows) and megaloblastic changes (dashed arrow)

Figure 4

The COX4I2 Mutation (A and B) Genomic fragment of the COX4I2 gene disclosing the c.412 G > A mutation (arrow) in a patient (A) and an obligate heterozygote (B). (C) normal control. (D) Conservation throughout evolution of the glutamic acid at codon 138 (bolded). D. Melano. stands for Drosophila melanogaster.