Abstrait

Mutation analysis of circadian clock gene BMAL1 in 21 Pakistani congenital cataract families

Udita Bagchi, Shazia Micheal, Sorath Noorani Siddiqui, Muhammad Imran Khan, Jacoline B Ten Brink, MariePaule Felder-Schmittbuhl and Arthur A Bergen

Background: Given the cataract phenotype in BMAL1-/- mice, we aimed to identify potential disease-causing variants in the human circadian clock candidate gene BMAL1 in 21 probands of consanguineous Pakistani congenital cataract families.

Methods: Ophthalmic examinations were performed for the probands and available family members. Genomic DNA was isolated from a volume of 5 ml of peripheral blood. The entire coding region of the candidate gene BMAL1 was analyzed in the probands of 21 families with targeted Sanger sequencing.

Results: A heterozygous missense variant c.41A>T; p.(Asp14Val) was detected in 1 of the 21 patients, which has a rare allele frequency of 0.000065 (2/30576 individuals) exclusively in the South-Asian population. The variant did not co-segregate with the disease phenotype in the family. A non-synonymous variant (rs2290037) in the heterozygous state was also identified in 5 out of 21 probands with a higher allele frequency of 0.1190 as compared to the global population (0.06626; 15570/234984 individuals).

Conclusion: Our study is the first to investigate the core circadian clock gene BMAL1 in humans for their association with congenital cataract. Unfortunately, no clear association between human genetic BMAL1 variants and cataract was found. Compared with targeted NGS technologies, traditional Sanger sequencing remains an indispensable cost-effective tool especially to report mutation profiles in small study cohorts. Our study may act to guide further studies in the molecular clockwork pathway from other (disease) populations.