Potentially lethal cystic fibrosis gene variant in the orangutan. Issue 12 (22nd January 2020)

• Record Type: Journal Article
• Authors: Taylor‐Cousar, Jennifer L.; Evans, Taylor A.; Cutting, Garry R.; Sharma, Neeraj
• Is Part Of: American journal of primatology. Volume 83:Issue 12(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-01-22
• Subjects: air sacculitis -- bronchiectasis -- cystic fibrosis transmembrane conductance regulator (CFTR) gene -- Pongo -- respiratory; Primates -- Periodicals; Primates -- Périodiques; 599.8
• DOI: 10.1002/ajp.23097
• Languages: English
• ISSNs: 0275-2565

Abstract

Abstract: A syndrome of chronic upper and lower airway disease leading to increased morbidity and mortality occurs primarily in captive orangutans. Similarities in symptoms to the inherited human respiratory disease, cystic fibrosis, led us to hypothesize that orangutan respiratory disease is a result of variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. We identified the nonsense variant, c.484A>T (p.Lys162X), in heterozygosity in an unaffected orangutan. Analysis of the pedigree of this orangutan confirmed that both his sire and deceased fetus also harbored the c.484A>T allele. An expression minigene harboring c.484A>T produced no full‐length CFTR protein in HEK293 cells. Finally, the c.484A>T CFTR messenger RNA abundance was severely reduced in primary nasal epithelial cells of the orangutan indicating that c.484A>T (p.Lys162X) is potentially lethal. Genetic screening of the captive orangutan population could be used to prevent transmission of this potentially lethal variant, and thus aid in the conservation of this critically endangered species. Abstract : An asymptomatic adult male orangutan (arrow) was identified to have the nonsense variant c.484A>T (p.Lys162X) in the heterozygous state. The mutation was determined to have been transmitted from his sire, and subsequently, the orangutan transmitted the mutation to his stillborn offspring. Based on the decreased CFTR protein production caused by this mutation, the nonsense variant p.Lys162X would be predicted to cause lethal cystic fibrosis respiratory disease in the orangutan if observed either in homozygosity or compound heterozygosity with another loss of function variant. Research Highlights: Chronic respiratory disease is an important cause of mortality in captive orangutans; variants in the cystic fibrosis gene could be one cause. We identified the nonsense variant, c.484A>T (p.Lys162X), in heterozygosity in an orangutan.