The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family.
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.
Hilhorst-Hofstee
Yvonne
Y
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. hilhorst@lumc.nl
Rijlaarsdam
Marry E B
ME
Scholte
Arthur J H A
AJ
Swart-van den Berg
Marietta
M
Versteegh
Michel I M
MI
van der Schoot-van Velzen
Iris
I
Schäbitz
Hans-Joachim
HJ
Bijlsma
Emilia K
EK
Baars
Marieke J
MJ
Kerstjens-Frederikse
Wilhelmina S
WS
Giltay
Jacques C
JC
Hamel
Ben C
BC
Breuning
Martijn H
MH
Pals
Gerard
G
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
D001224:Aspartic Acid; D004815:Epidermal Growth Factor; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines