Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital CataractsReportar como inadecuado




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Purpose

To identify the molecular basis of non-syndromic autosomal recessive congenital cataracts arCC in a consanguineous family.

Methods

All family members participating in the study received a comprehensive ophthalmic examination to determine their ocular phenotype and contributed a blood sample, from which genomic DNA was extracted. Available medical records and interviews with the family were used to compile the medical history of the family. The symptomatic history of the individuals exhibiting cataracts was confirmed by slit-lamp biomicroscopy. A genome-wide linkage analysis was performed to localize the disease interval. The candidate gene, LIM2 lens intrinsic membrane protein 2, was sequenced bi-directionally to identify the disease-causing mutation. The physical changes caused by the mutation were analyzed in silico through homology modeling, mutation and bioinformatic algorithms, and evolutionary conservation databases. The physiological importance of LIM2 to ocular development was assessed in vivo by real-time expression analysis of Lim2 in a mouse model.

Results

Ophthalmic examination confirmed the diagnosis of nuclear cataracts in the affected members of the family; the inheritance pattern and cataract development in early infancy indicated arCC. Genome-wide linkage analysis localized the critical interval to chromosome 19q with a two-point logarithm of odds LOD score of 3.25. Bidirectional sequencing identified a novel missense mutation, c.233G>A p.G78D in LIM2. This mutation segregated with the disease phenotype and was absent in 192 ethnically matched control chromosomes. In silico analysis predicted lower hydropathicity and hydrophobicity but higher polarity of the mutant LIM2-encoded protein MP19 compared to the wild-type. Moreover, these analyses predicted that the mutation would disrupt the secondary structure of a transmembrane domain of MP19. The expression of Lim2, which was detected in the mouse lens as early as embryonic day 15 E15 increased after birth to a level that was sustained through the postnatal time points.

Conclusion

A novel missense mutation in LIM2 is responsible for autosomal recessive congenital cataracts.



Autor: Bushra Irum, Shahid Y. Khan, Muhammad Ali, Haiba Kaul, Firoz Kabir, Bushra Rauf, Fareeha Fatima, Raheela Nadeem, Arif O. Khan, Sa

Fuente: http://plos.srce.hr/



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