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Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts
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 sam...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096708/ https://www.ncbi.nlm.nih.gov/pubmed/27814360 http://dx.doi.org/10.1371/journal.pone.0162620 |
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author | Irum, Bushra Khan, Shahid Y. Ali, Muhammad Kaul, Haiba Kabir, Firoz Rauf, Bushra Fatima, Fareeha Nadeem, Raheela Khan, Arif O. Al Obaisi, Saif Naeem, Muhammad Asif Nasir, Idrees A. Khan, Shaheen N. Husnain, Tayyab Riazuddin, Sheikh Akram, Javed Eghrari, Allen O. Riazuddin, S. Amer |
author_facet | Irum, Bushra Khan, Shahid Y. Ali, Muhammad Kaul, Haiba Kabir, Firoz Rauf, Bushra Fatima, Fareeha Nadeem, Raheela Khan, Arif O. Al Obaisi, Saif Naeem, Muhammad Asif Nasir, Idrees A. Khan, Shaheen N. Husnain, Tayyab Riazuddin, Sheikh Akram, Javed Eghrari, Allen O. Riazuddin, S. Amer |
author_sort | Irum, Bushra |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5096708 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50967082016-11-18 Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts Irum, Bushra Khan, Shahid Y. Ali, Muhammad Kaul, Haiba Kabir, Firoz Rauf, Bushra Fatima, Fareeha Nadeem, Raheela Khan, Arif O. Al Obaisi, Saif Naeem, Muhammad Asif Nasir, Idrees A. Khan, Shaheen N. Husnain, Tayyab Riazuddin, Sheikh Akram, Javed Eghrari, Allen O. Riazuddin, S. Amer PLoS One Research Article 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. Public Library of Science 2016-11-04 /pmc/articles/PMC5096708/ /pubmed/27814360 http://dx.doi.org/10.1371/journal.pone.0162620 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Irum, Bushra Khan, Shahid Y. Ali, Muhammad Kaul, Haiba Kabir, Firoz Rauf, Bushra Fatima, Fareeha Nadeem, Raheela Khan, Arif O. Al Obaisi, Saif Naeem, Muhammad Asif Nasir, Idrees A. Khan, Shaheen N. Husnain, Tayyab Riazuddin, Sheikh Akram, Javed Eghrari, Allen O. Riazuddin, S. Amer Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts |
title | Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts |
title_full | Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts |
title_fullStr | Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts |
title_full_unstemmed | Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts |
title_short | Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts |
title_sort | mutation in lim2 is responsible for autosomal recessive congenital cataracts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096708/ https://www.ncbi.nlm.nih.gov/pubmed/27814360 http://dx.doi.org/10.1371/journal.pone.0162620 |
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