Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus. (February 2019)

• Record Type: Journal Article
• Authors: Macdonald, Gemma C.; Hesselson, Stephanie E.; Chan, Jeng Yie; Jenkins, Arthur B; Laybutt, D. Ross; Hesselson, Daniel; Campbell, Lesley V.
• Is Part Of: Diabetes research and clinical practice. Volume 148(2019)
• Page Start: 64
• Page End: 71
• Publication Date: 2019-02
• Subjects: Insulin-treated diabetes -- Aniridia -- Familial genetics -- Diabetes diagnosis; Diabetes -- Periodicals; Diabetes Mellitus -- Periodicals; 616.462
• DOI: 10.1016/j.diabres.2018.12.002
• Languages: English
• ISSNs: 0168-8227

Abstract

Highlights: Developmental gene PAX6 affects pancreatic and eye formation (aniridia). Distal PAX6 enhancer region deletion segregates with diabetes and aniridia. Clinically distinct from previous reports describing aniridia and glucose intolerance. Aniridia patients with distal PAX6 deletions require early screening for diabetes. Abstract: Aims: Analyze cosegregation of aniridia and diabetes to identify genetic criteria for detection and early treatment of diabetes-susceptible aniridia patients. Methods: We assessed a two-generation family: three individuals with aniridia, two previously diagnosed as type 2 diabetes. One individual with aniridia, with unknown diabetes status, was evaluated by oral glucose tolerance test. Genetic analysis of aniridia-associated genes was performed on all available family members. Candidate genes were functionally tested by gene silencing in MIN6 pancreatic β-cells. Results: A 25 year old male with aniridia had a diabetic oral glucose tolerance test despite a normal fasting blood glucose. A 484–630 kb deletion ∼120 kb distal to PAIRED BOX 6 ( PAX6 ) showed dominant cosegregation with aniridia and diabetes in all affected family members. The deleted region contains regulatory elements for PAX6 expression and four additional coding regions. Knockdown of two of the deleted genes ( Dnajc24 or Immp1l ) with Pax6 impaired glucose-stimulated insulin secretion. Conclusions: We demonstrate dominant cosegregation of diabetes and aniridia with a deletion distal to PAX6, which is clinically distinct from the mild glucose intolerance previously reported with PAX6 coding mutations. Asymptomatic aniridia individuals appear at risk of diabetes (and its complications) and could benefit from earlier diagnosis and treatment.