title: Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype.
abstract: Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, respectively. All the identified CCA mutations in FBN2 cluster in a limited region similar to where severe MFS mutations cluster in FBN1, specifically between exons 23 and 34. We screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing. We successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this limited region. Interestingly, none of these identified FBN2 mutations alter amino acids in the calcium binding consensus sequence in the EGF-like domains, whereas many of the FBN1 mutations alter the consensus sequence. Furthermore, analysis of the clinical data of the CCA patients with characterized FBN2 mutation indicate that CCA patients have aortic root dilatation and the vast majority lack evidence of congenital heart disease. These studies have implications for our understanding of the molecular basis of CCA, along with the diagnosis and genetic counseling of CCA patients.
authors.affiliation: Department of Internal Medicine, University of Texas-Houston Medical School, Houston, Texas, USA.
authors.forename: Prateek A
authors.initials: PA
authors.lastname: Gupta
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Putnam
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Carmical
authors.forename: Ilkka
authors.initials: I
authors.lastname: Kaitila
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Anne
authors.initials: A
authors.lastname: Child
authors.forename: Cesare
authors.initials: C
authors.lastname: Danesino
authors.forename: Kay
authors.initials: K
authors.lastname: Metcalfe
authors.forename: Susan A
authors.initials: SA
authors.lastname: Berry
authors.forename: Emily
authors.initials: E
authors.lastname: Chen
authors.forename: Catherine Vincent
authors.initials: CV
authors.lastname: Delorme
authors.forename: Meow-Keong
authors.initials: MK
authors.lastname: Thong
authors.forename: Lesley C
authors.initials: LC
authors.lastname: Adès
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D054392:Adipokines
chemical_list: D002135:Calcium-Binding Proteins; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human