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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
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.
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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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