title: Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients.
abstract: Ectopia lentis (EL) is genetically heterogeneous with both autosomal-dominant and -recessive forms. The dominant disorder can be caused by mutations in FBN1, at the milder end of the type-1 fibrillinopathies spectrum. Recently in a consanguineous Jordanian family, recessive EL was mapped to locus 1q21 containing the ADAMTSL4 gene and a nonsense mutation was found in exon 11 (c.1785T>G, p.Y595X). In this study, 36 consecutive probands with EL who did not fulfill the Ghent criteria for MFS were screened for mutations in FBN1 and ADAMTSL4. Causative FBN1 mutations were identified in 23/36 (64%) of probands while homozygous or compound heterozygous ADAMTSL4 mutations were identified in 6/12 (50%) of the remaining probands. Where available, familial screening of these families confirmed the mutation co-segregated with the EL phenotype. This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal-recessive EL in British families. Furthermore; the first compound heterozygous mutation is described resulting in a PTC and a missense mutation in the PLAC (protease and lacunin) domain. The identification of a causative mutation in ADAMTSL4 may allow the exclusion of Marfan syndrome in these families and guide the clinical management, of particular relevance in young children affected by EL.
authors.affiliation: Sonalee Laboratory, Cardiac & Vascular Sciences, St George's University of London, SW17 0RE, UK. garno@sgul.ac.uk
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Aragon-Martin
authors.forename: Dana
authors.initials: D
authors.lastname: Ahnood
authors.forename: David G
authors.initials: DG
authors.lastname: Charteris
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.forename: Ken K
authors.initials: KK
authors.lastname: Nischal
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.forename: Aman
authors.initials: A
authors.lastname: Chandra
authors.forename: Anne H
authors.initials: AH
authors.lastname: Child
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
mesh_terms: D000071096:ADAMTS Proteins; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004479:Ectopia Lentis / Q000235:genetics*; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D019699:Thrombospondins / Q000235:genetics*; D054392:Adipokines
chemical_list: D000071096:ADAMTS Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D019699:Thrombospondins; C486779:ADAMTSL4 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines