Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts.
OBJECTIVE
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.


CONCLUSIONS
A novel missense mutation in LIM2 is responsible for autosomal recessive congenital cataracts.
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.|National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Bushra
B
Irum
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
Shahid Y
SY
Khan
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
Muhammad
M
Ali
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
Haiba
H
Kaul
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
Firoz
F
Kabir
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.|National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Bushra
B
Rauf
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Fareeha
F
Fatima
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Raheela
R
Nadeem
King Khaled Eye Specialist Hospital, Riyadh, 12329, Saudi Arabia.
Arif O
AO
Khan
King Khaled Eye Specialist Hospital, Riyadh, 12329, Saudi Arabia.
Saif
S
Al Obaisi
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Muhammad Asif
MA
Naeem
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Idrees A
IA
Nasir
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Shaheen N
SN
Khan
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
Tayyab
T
Husnain
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.|Allama Iqbal Medical College, University of Health Sciences, Lahore, 54550, Pakistan.|National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, 44000, Pakistan.
Sheikh
S
Riazuddin
Allama Iqbal Medical College, University of Health Sciences, Lahore, 54550, Pakistan.|National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, 44000, Pakistan.
Javed
J
Akram
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
Allen O
AO
Eghrari
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, United States of America.
S Amer
SA
Riazuddin
D000818:Animals; D002386:Cataract / Q000235:genetics*; D003241:Consanguinity; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D040941:Heredity / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree
D005136:Eye Proteins; C044539:LIM2 protein, human; D008565:Membrane Proteins