title: FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited.
abstract: The recent identification of TGFBR2 mutations in Marfan syndrome II (MFSII) [Mizuguchi et al. (2004); Nat Genet 36:855-860] and of TGFBR1 and TGFBR2 mutations in Loeys-Dietz aortic aneurysm syndrome (LDS) [Loeys et al. (2005); Nat Genet 37:275-281] [OMIM 609192] has provided direct evidence of abnormal signaling in transforming growth factors beta (TGF-beta) in the pathogenesis of Marfan syndrome (MFS). In light of this, we describe the phenotypes and genotypes of five individuals. Patient 1 had MFS and abnormal cranial dura. Patient 2 had severe early onset MFS and an abnormal skull. Patients 3 and 4 had probable Furlong syndrome (FS). Patient 5 had marfanoid (MD) features, mental retardation (MR), and a deletion of chromosome 15q21.1q21.3. All patients had a condition within the MFS, MD-craniosynostosis (CS) or MD-MR spectrum. The names of these entities may become redundant, and instead, come to be considered within the spectrum of TGF-beta signaling pathway disorders. Two recurrent heterozygous FBN1 mutations were found in Patients 1 and 2, and an identical novel heterozygous de novo TGFBR1 mutation was found in Patients 3 and 4, in whom altered fibrillin-1 processing was demonstrated previously [Milewicz et al. (2000); Am J Hum Genet 67:279]. A heterozygous FBN1 deletion was found in Patient 5. These findings support the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abnormal TGF-beta signaling is the core pathogenetic mechanism in MFS and related entities including the MD-CS syndromes.
authors.affiliation: Marfan Research Group, The Children's Hospital at Westmead, New South Wales, Australia. lesleya@chw.edu.au
authors.forename: L C
authors.initials: LC
authors.lastname: Adès
authors.forename: K
authors.initials: K
authors.lastname: Sullivan
authors.forename: A
authors.initials: A
authors.lastname: Biggin
authors.forename: E A
authors.initials: EA
authors.lastname: Haan
authors.forename: M
authors.initials: M
authors.lastname: Brett
authors.forename: K J
authors.initials: KJ
authors.lastname: Holman
authors.forename: J
authors.initials: J
authors.lastname: Dixon
authors.forename: S
authors.initials: S
authors.lastname: Robertson
authors.forename: A D
authors.initials: AD
authors.lastname: Holmes
authors.forename: J
authors.initials: J
authors.lastname: Rogers
authors.forename: B
authors.initials: B
authors.lastname: Bennetts
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D030201:Activin Receptors, Type I / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002872:Chromosome Deletion; D003398:Craniosynostoses / Q000473:pathology*; D004252:DNA Mutational Analysis; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000473:pathology*; D008297:Male; D008382:Marfan Syndrome / Q000473:pathology*; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D013577:Syndrome; D054392:Adipokines
chemical_list: D030201:Activin Receptors, Type I; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000625841:TGFBR1 protein, human