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Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus


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 beta-cells. RESULTS: A 25year old male with aniridia had a diabetic oral glucose tolerance test despite a normal fasting blood glucose. A 484-630kb deletion approximately 120kb 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.

Type Journal
ISBN 1872-8227 (Electronic) 0168-8227 (Linking)
Authors Macdonald, G. C.; Hesselson, S. E.; Chan, J. Y.; Jenkins, A. B.; Laybutt, D. R.; Hesselson, D.; Campbell, L. V.
Responsible Garvan Author Prof Lesley Campbell
Published Date 2018-12-21
Published Volume 148
Published Pages 64-71
Status Published in-print
DOI 10.1016/j.diabres.2018.12.002
URL link to publisher's version
OpenAccess link to author's accepted manuscript version