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• W2040470498 abstract "Ectopia lentis often occurring in association with Marfan's syndrome, Weill–Marchesani's syndrome or homocystinuria (Chandra et al. 2014), has been named ‘isolated non-syndromic ectopia lentis’ (IEL), if it did not occur in association with any apparent systemic disease. Eyes with IEL usually show additional other ocular disorders including cataract, retinal detachment and myopia (Bjerrum & Kessing 1991). IEL was reported to be inherited in an either autosomal dominant pattern (OMIM 129600) or autosomal recessive manner (OMIM 225100) (Ahram et al. 2009). Mutations in the fibrillin 1 (FBN1) gene (OMIM 134797) and the ADAMTSL4 gene (OMIM 610113) were usually responsible (Ades et al. 2004; Ahram et al. 2009). Recently, truncating mutations in the LTBP2 gene were reported as an additional cause of autosomal recessive ectopia lentis as a primary or secondary characteristics in patients with other ocular manifestations (e.g. primary congenital glaucoma) and extraocular manifestations (e.g. marfanoid stature) (Azmanov et al. 2011). Some of the patients with these mutations originated from a Roma/Gypsy founder population. Disease-causing mutation in the ADAMTSL4 gene was first identified by Ahram et al. (2009). Here, we report on a Chinese family in which novel compound heterozygous c.1783dupT and c.2594 G>A mutations of the ADAMTSL4 gene were identified in all affected members. The study included a Chinese family with IEL with autosomal recessive inheritance. The study was approved by the Medical Ethics Committee of the West China Hospital of Sichuan University. Informed consent was obtained from all participants. Family recruitment and clinical examination included nine members of two generations in this family. Four family members of seven of the second generation were affected. Poor vision since childhood was noticed in all affected individuals. Proband II:1, a 21-year-old man (Fig. 1A,B) presented with bilateral lens subluxation into the temporal direction and lens opacity. The left eye additionally showed signs of a secondary-lens-induced pupillary block glaucoma with an intraocular pressure of 51 mmHg and secondary iris atrophy. The axial length of the right eye was 25.09 mm. Patient II:3 was a 15-year-old girl (Fig. 1C,D) who presented with bilateral lens subluxation and punctate cortical lens opacities. Axial length was 25.72 mm OD and 26.21 mm OS. Patient II:5 was a 9-year-old girl (Fig. 1E,F) who presented with bilateral lens subluxation and cataract. Axial length was 24.86 mm OD and 25.21 mm OS. Patient II:6 was a 7-year-old boy (Fig. 1G,H) who presented with bilateral lens subluxation and with an axial length of 22.07 mm OD and 20.29 mm OS. In none of the patients, skeletal, cardiovascular or other physical abnormalities were detected. All other family members and 100 control subjects were unremarkable with respect to their ocular and general physical examination. Genomic DNA was extracted from peripheral blood leucocytes for genetic analysis. The ADAMTSL4 mutation identification and analysis revealed that a heterozygous mutation c.1783dupT in exon 11 of ADAMTSL4 and a heterozygous c. 2594G>A mutation in exon 16 of ADAMTSL4 were identified in all patients affected by IEL. The c.1783dupT mutation which was inherited from the father led to a frameshift that truncated the open reading frame (ORF) by creating a premature stop codon (TGA) 38-bp downstream of the duplication site and generated a protein of 606 amino acids consequently. The c.2594G>A mutation, inherited from the mother, led to an amino acid substitution from arginine (CGC) to histidine (CAC) at position 865 (p.Arg865His). Family members who carried none or only one of these two mutations did not exhibit any abnormal phenotype, indicating that the compound heterozygous c.1783dupT and c. 2594G>A mutations of ADAMTSL4 gene were causative mutations for this family with IEL. None of these mutations were detected in the 100 normal control subjects. The bioinformatics analysis revealed that amino acids at both mutational sites were highly conserved for ADAMTSL4 based on the analysis of orthologues from ten different species using the Clustalw tool online. The c.2594G>A mutation was predicted to be ‘probably damaging’ with the highest score by the HumDiv model of Polymorphism Phenotyping v2 (PolyPhen-2) and was predicted to be ‘damaging’ with a reliable score of 0.00 by Sorting Intolerant From Tolerant (SIFT). The human ADAMTSL4 (Gene ID: 54507) gene, also named as TSRC1, was mapped on chromosome 1q21 in 2003 (Buchner & Meisler 2003). To date, 15 mutations of the ADAMTSL4 gene have been identified in patients with ectopia lentis. Most patients carrying the ADAMTSL4 mutations were mainly of European ethnicity. Our report is the first investigation on Asian patients with IEL in general. All of the mutations reported so far were homozygous or compound heterozygous state, and the mutations did not cause IEL in heterozygous carriers, indicating that the pathogenesis of IEL was correlated with the effect of the gene dosage. The patients who had two defective alleles of the ADAMTSL4 gene may be more vulnerable to disease. Neither mutation on its own was sufficient to cause IEL. The novelty of the findings of our study is essentially based on the fact that few mutations have been so far identified in the gene, and that for the first time, these two mutations have been found at a compound heterozygous state in all affected subjects in a large Chinese pedigree." @default.
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• W2040470498 date "2014-05-07" @default.
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• W2040470498 title "Novel compound heterozygous mutations identified in<i>ADAMTSL4</i>gene in a Chinese family with isolated ectopia lentis" @default.
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• W2040470498 doi "https://doi.org/10.1111/aos.12399" @default.
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