Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts

Irum, Bushra; Khan, Shahid Y.; Ali, Muhammad; Kaul, Haiba; Kabir, Firoz; Rauf, Bushra; Fareeha, Fatima; Nadeem, Raheela; Khan, Arif O.; Obaisi, Saif Al; Naeem, Muhammad Asif; Nasir, Idrees A.; Khan, Shaheen N.; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O.

doi:10.1371/journal.pone.0162620

Cited by 20 publications

(12 citation statements)

References 27 publications

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“…LIM2 belongs to a group of small integral membrane glycoproteins with a crucial role in lens biology, cytoskeletal integrity, cell morphology and intercellular communication [ 26 ]. The product of LIM2 is a 173-amino-acid membrane protein named MIP20 (alternatively known as MP17/MP18/MP19), the second most abundant integral membrane protein of the ocular lens fiber cells of vertebrates [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Fernández-Alcalde

Nieves-Moreno

Noval

et al. 2021

Genes

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Our purpose was to identify mutations responsible for non-syndromic congenital cataracts through the implementation of next-generation sequencing (NGS) in our center. A sample of peripheral blood was obtained from probands and willing family members and genomic DNA was extracted from leukocytes. DNA was analyzed implementing a panel (OFTv2.1) including 39 known congenital cataracts disease genes. 62 probands from 51 families were recruited. Pathogenic or likely pathogenic variants were identified in 32 patients and 25 families; in 16 families (64%) these were de novo mutations. The mutation detection rate was 49%. Almost all reported mutations were autosomal dominant. Mutations in crystallin genes were found in 30% of the probands. Mutations in membrane proteins were detected in seven families (two in GJA3 and five in GJA8). Mutations in LIM2 and MIP were each found in three families. Other mutations detected affected EPHA2, PAX6, HSF4 and PITX3. Variants classified as of unknown significance were found in 5 families (9.8%), affecting CRYBB3, LIM2, EPHA2, ABCB6 and TDRD7. Mutations lead to different cataract phenotypes within the same family.

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Section: Resultsmentioning

confidence: 99%

Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Fernández-Alcalde

Nieves-Moreno

Noval

et al. 2021

Genes

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“…[32][33][34] Three LIM2 missense mutations have been described that cause autosomal recessive cataract (1) c.313T>G, p.(Phe105Val) mutation associated with cortical cataract; (2) c.587G>A, p.(Gly154Glu) mutation in a family causing autosomal recessive cataract; and (3) c.233G>A, p.(Gly78Asp) mutation in a consanguineous Pakistani family with nuclear cataracts. 35,36 Other proteins working at the membrane include EPHA2 and DNMBP. EPHA2 encodes a membrane-bound protein tyrosine kinase, 37 and mutations have been shown to account for approximately 5% of inherited cataracts in the Australian population.…”

Section: Inherited Cataractmentioning

confidence: 99%

Congenital cataract: a guide to genetic and clinical management

Bell

Oluonye

Harding³

et al. 2020

Therapeutic Advances in Rare Disease

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Worldwide 20,000–40,000 children with congenital or childhood cataract are born every year with varying degrees and patterns of lens opacification with a broad aetiology. In most cases of bilateral cataract, a causative genetic mutation can be identified, with autosomal dominant inheritance being most common in 44% of cases. Variants in genes involve lens-specific proteins or those that regulate eye development, thus giving rise to other associated ocular abnormalities. Approximately 15% of cases have systemic features, hence paediatric input is essential to minimise comorbidities and support overall development of children at high risk of visual impairment. In some metabolic conditions, congenital cataract may be the presenting sign, and therefore prompt diagnosis is important where there is an available treatment. Multidisciplinary management of children is essential, including ophthalmic surgeons, orthoptists, paediatricians, geneticists and genetic counsellors, and should extend beyond the medical team to include school and local paediatric visual support services. Early surgery and close follow up in ophthalmology is important to optimise visual potential and prevent amblyopia. Routine genetic testing is essential for the complete clinical management of patients, with next-generation sequencing of 115 genes shown to expedite molecular diagnosis, streamline care pathways and inform genetic counselling and reproductive options for the future. Lay title Childhood cataract: how to manage patients Lay abstract Cataract is a clouding of the lens in the eye. Cataract occurring in children has many different causes, which may include infections passed from mother to child during pregnancy, trauma, medications and exposure to radiation. In most cases of cataract occurring in both eyes, a genetic cause can be found which may be inherited from parents or occur sporadically in the developing baby itself while in the womb. Cataracts may occur on their own, with other eye conditions or be present with other disorders in the body as part of a syndrome. Genetic testing is important for all children with cataract as it can provide valuable information about cause, inheritance and risk to further children and signpost any other features of the disease in the rest of the body, permitting the assembly of the correct multidisciplinary care team. Genetic testing currently involves screening for mutations in 115 genes already known to cause cataract and has been shown to expedite diagnosis and help better manage children. Genetic counselling services can support families in understanding their diagnosis and inform future family planning. In order to optimise vision, early surgery for cataract in children is important. This is because the brain is still developing and an unobstructed pathway for light to reach the back of the eye is required for normal visual development. Any obstruction (such as cataract) if left untreated may lead to permanent sight impairment or blindness, even if it is removed later. A multidisciplinary team involved in the care of a child with cataract should include ophthalmic surgeons, orthoptists, paediatricians, geneticists and genetic counsellors, and should extend beyond the medical team to include school and local child visual support services. They will help to diagnose and manage systemic conditions, optimise vision potential and help patients and their families access best supportive care.

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“…Currently, over 48 genes have been identified underlying congenital cataract. About 50% of the families have pathogenic mutations in crystalline genes; almost 25% have changes in the connexin genes [ 5 ]; and the remainder have causative mutations in genes such as aquaporin ( MIP ) [ 6 ], beaded filament structural protein 2 ( BFSP2 ) [ 7 ], paired-like homeodomain 3 ( PITX3 ) [ 8 ], avian musculoaponeurotic fibrosarcoma ( MAF ) [ 9 ], heat shock transcription factor 4 gene ( HSF4 ) [ 10 ], lens intrinsic membrane protein ( LIM2) [ 11 ], glucosaminyl ( N -acetyl) transferase 2 ( GCNT2) [ 12 ] as well as many others, as delineated in the Cat-Map database [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Delineation of Novel Autosomal Recessive Mutation in GJA3 and Autosomal Dominant Mutations in GJA8 in Pakistani Congenital Cataract Families

Micheal

Niewold

Siddiqui³

et al. 2018

Genes

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Congenital cataract is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic cause of congenital cataract families. DNA samples of a large consanguineous Pakistani family were genotyped with a high resolution single nucleotide polymorphism Illumina microarray. Homozygosity mapping identified a homozygous region of 4.4 Mb encompassing the gene GJA3. Sanger sequence analysis of the GJA3 gene revealed a novel homozygous variant c.950dup p.(His318ProfsX8) segregating in an autosomal recessive (AR) manner. The previously known mode of inheritance for GJA3 gene mutations in cataract was autosomal dominant (AD) only. The screening of additional probands (n = 41) of cataract families revealed a previously known mutation c.56C>T p.(Thr19Met) in GJA3 gene. In addition, sequencing of the exon-intron boundaries of the GJA8 gene in 41 cataract probands revealed two additional mutations: a novel c.53C>T p.(Ser18Phe) and a known c.175C>G p.(Pro59Ala) mutation, both co-segregating with the disease phenotype in an AD manner. All these mutations are predicted to be pathogenic by in silico analysis and were absent in the control databases. In conclusion, results of the current study enhance our understanding of the genetic basis of cataract, and identified the involvement of the GJA3 in the disease etiology in both AR and AD manners.

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Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts

Cited by 20 publications

References 27 publications

Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Congenital cataract: a guide to genetic and clinical management

Delineation of Novel Autosomal Recessive Mutation in GJA3 and Autosomal Dominant Mutations in GJA8 in Pakistani Congenital Cataract Families

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