title: The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family.
abstract: Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. hilhorst@lumc.nl
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hilhorst-Hofstee
authors.forename: Marry E B
authors.initials: ME
authors.lastname: Rijlaarsdam
authors.forename: Arthur J H A
authors.initials: AJ
authors.lastname: Scholte
authors.forename: Marietta
authors.initials: M
authors.lastname: Swart-van den Berg
authors.forename: Michel I M
authors.initials: MI
authors.lastname: Versteegh
authors.forename: Iris
authors.initials: I
authors.lastname: van der Schoot-van Velzen
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schäbitz
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.forename: Marieke J
authors.initials: MJ
authors.lastname: Baars
authors.forename: Wilhelmina S
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.forename: Jacques C
authors.initials: JC
authors.lastname: Giltay
authors.forename: Ben C
authors.initials: BC
authors.lastname: Hamel
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics*; D002648:Child; D004815:Epidermal Growth Factor / Q000737:chemistry*; D005190:Family; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D055815:Young Adult; D054392:Adipokines
chemical_list: D001224:Aspartic Acid; D004815:Epidermal Growth Factor; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines