Gemma C Macdonald1, Stephanie E Hesselson2, Jeng Yie Chan3, Arthur B Jenkins4, D Ross Laybutt3, Daniel Hesselson5, Lesley V Campbell6. 1. Diabetes Centre, St Vincent's Hospital, Sydney, New South Wales, Australia. Electronic address: gemma_macdonald28@hotmail.com. 2. Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. 3. Diabetes and Metabolism Division, Garvan Institute of Medical Research, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, NSW, Australia. 4. School of Medicine, University of Wollongong, Wollongong, Australia. 5. Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Australia. Electronic address: d.hesselson@garvan.org.au. 6. Diabetes Centre, St Vincent's Hospital, Sydney, New South Wales, Australia; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Australia; Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.
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.
AIMS: Analyze cosegregation of aniridia and diabetes to identify genetic criteria for detection and early treatment of diabetes-susceptible aniridiapatients. 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.