Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.
ABSTRACT Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.
SourceAvailable from: Jose Antonio Aragon-Martin[Show abstract] [Hide abstract]
ABSTRACT: ADAMTSL4 nega(ve , 16 FBN1 Unknown & ADAMTSL4 nega(ve, 7 Gene(c carriers, 19 Compound heterozygotes, 12 Homozygotes, 20 ADAMTSL4 posi(ve, 51 Diagram of negative and positive ADAMTSL4 mutation Fig.5 This study supports the evidence that homozygous and compound heterozygous mutations in ADAMTSL4 cause autosomal recessive EL, therefore demonstrating that ADAMTSL4 could play a key role in the development and/or integrity of the zonular fibers. The identification of a causative mutation in ADAMTSL4 will exclude Marfan syndrome in EL patients and guide clinical management, of particular relevance in young children affected with EL. In our EL population we screen first for FBN1 mutations in marfanoid patients with autosomal dominant pedigrees, and first for ADAMTSL4 in apparently autosomal recessive pedigrees. Exome sequencing Ectopia Lentis patients can be the next strategy. It is a cheaper technique with a great scope and can help research on modifier genes, as well as screening other candidate EL genes (ADAMTS10, ADAMTS17, LTBP2).American Society of Human Genetics (ASHG), San Diego, CA, USA; 10/2014
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ABSTRACT: Background: Ectopia Lentis (EL) is clinically and genetically heterogeneous (autosomal dominant - MIM 129600; autosomal recessive - MIM 225100). The dominant form can arise through mutations in FBN1 (Comeglio et al. 2007), at the milder end of the type-1 fibrillinopathy spectrum. The recessive form has been shown to be caused by ADAMTSL4 mutations (Aragon et al. 2010). EL is characterized by the disruption of the zonular fibers. In time, the lens moves out of place causing lens subluxation. Methods: Seventy-five UK patients with isolated EL were bidirectionally Sanger sequenced for mutations in the coding exons including intron/exon boundaries of ADAMTSL4 gene. The patients did not fulfill the Ghent criteria for Marfan syndrome & 55/75 (73%) were FBN1 negative. When possible, compound heterozygotes were confirmed by family screening. Mutations were based on the transcript NM_019032. Genome databases (1000Genome & EVS) and in-silico tools (GVGD, Mutation T@ster, Polyphene-2, SIFT, BDGP & ESE_finder) were used to help with the analysis of the mutations. Results: Mutations in ADAMTSL4 were found in 51/75 (68%) samples. Genetic Carriers – 19/75 (25%). Compound Heterozygotes – 12/75 (16%). Homozygotes – 20/75 (27%). Novel mutations: 2 homozygotes – [Exon6: c.963dupG/p.T322Dfs*10] & [Exon16: c.2574_2580dupTGGGACG/p.G861Wfs*41]; 1 compound heterozygote – [Exon6: c.888delG/p.R297Dfs*46 & Exon16: c.2594G>A/p.R865H]; and 1 compound heterozygote involving a splice site – [Exon14: c.2270dupG/p.G758Wfs*59 & Exon15: c.2383-1G>C/splice site]. The mutation p.R865H has been found so far as compound heterozygote in 4 patients; and once in an unaffected genetic carrier, parent of a compound heterozygote proband in our cohort. Conclusions: This study supports the evidence that homozygous and compound heterozygous mutations in ADAMTSL4 cause autosomal recessive EL, therefore demonstrating that ADAMTSL4 could play a key role in the development and/or integrity of the zonular fibers. The identification of a causative mutation in ADAMTSL4 will exclude Marfan syndrome in EL patients and guide clinical management, of particular relevance in young children affected with EL. In our EL population we screen first for FBN1 mutations in marfanoid patients with autosomal dominant pedigrees, and first for ADAMTSL4 in apparently autosomal recessive pedigrees. Corresponding author: firstname.lastname@example.org Support: Rosetrees Trust, Moorfields Eye Hospital Trustees, Special Trustees of Moorfields Eye Hospital, Marfan Trust, Roseborough Legacy, Specsavers, St. George's University of London.American Society Of Human Genetics (ASHG), San Diego, CA, USA; 10/2014
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ABSTRACT: Abstract Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, and intraocular pressure (IOP) is an important modifiable risk factor. IOP is a function of aqueous humor production and aqueous humor outflow, and it is thought that prolonged IOP elevation leads to optic nerve damage over time. Within the trabecular meshwork (TM), the eye's primary drainage system for aqueous humor, matricellular proteins generally allow cells to modulate their attachments with and alter the characteristics of their surrounding extracellular matrix (ECM). It is now well established that ECM turnover in the TM affects outflow facility, and matricellular proteins are emerging as significant players in IOP regulation. The formalized study of matricellular proteins in TM has gained increased attention. Secreted protein acidic and rich in cysteine (SPARC), myocilin, connective tissue growth factor (CTGF), and thrombospondin-1 and -2 (TSP-1 and -2) have been localized to the TM, and a growing body of evidence suggests that these matricellular proteins play an important role in IOP regulation and possibly the pathophysiology of POAG. As evidence continues to emerge, these proteins are now seen as potential therapeutic targets. Further study is warranted to assess their utility in treating glaucoma in humans.Journal of Ocular Pharmacology and Therapeutics 06/2014; 30(6). DOI:10.1089/jop.2014.0013 · 1.42 Impact Factor