Clustering of mutations associated with mild Marfan-like phenotypes in the 3' region of FBN1 suggests a potential genotype-phenotype correlation
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Clustering of mutations associated with mild Marfan-like phenotypes in the 3' region of FBN1 suggests a potential genotype-phenotype correlation. / Palz, M; Tiecke, F; Booms, P; Göldner, B; Rosenberg, T; Fuchs, J; Skovby, F; Schumacher, H; Kaufmann, U C; von Kodolitsch, Y; Nienaber, C A; Leitner, C; Katzke, S; Vetter, B; Hagemeier, C; Robinson, P N.
in: Am J Med Genet, Jahrgang 91, Nr. 3, 20.03.2000, S. 212-221.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Clustering of mutations associated with mild Marfan-like phenotypes in the 3' region of FBN1 suggests a potential genotype-phenotype correlation
AU - Palz, M
AU - Tiecke, F
AU - Booms, P
AU - Göldner, B
AU - Rosenberg, T
AU - Fuchs, J
AU - Skovby, F
AU - Schumacher, H
AU - Kaufmann, U C
AU - von Kodolitsch, Y
AU - Nienaber, C A
AU - Leitner, C
AU - Katzke, S
AU - Vetter, B
AU - Hagemeier, C
AU - Robinson, P N
N1 - Copyright 2000 Wiley-Liss, Inc.
PY - 2000/3/20
Y1 - 2000/3/20
N2 - Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, a dominantly inherited disorder of connective tissue that primarily involves the cardiovascular, ocular, and skeletal systems. There is a remarkable degree of variability both within and between families with Marfan syndrome, and FBN1 mutations have also been found in a range of other related connective tissue disorders collectively termed type-1 fibrillinopathies. FBN1 mutations have been found in almost all of the 65 exons of the FBN1 gene and for the most part have been unique to one affected patient or family. Aside from the "hot spots" for the neonatal Marfan syndrome in exons 24-27 and 31-32, genotype-phenotype correlations have been slow to emerge. Here we present the results of temperature-gradient gel electrophoresis analysis of FBN1 exons 59-65. Six mutations were identified, only one of which had been previously reported. Two of the six mutations were found in patients with mild phenotypes. Taken together with other published reports, our results suggest that a sizable subset (ca. 40%) of mutations in this region is associated with mild phenotypes characterized by the lack of significant aortic pathology, compared with about 7% in the rest of the gene. In two cases, mutations affecting analogous positions within one of the 43 cbEGF modules of FBN1 are associated with mild phenotypes when found in one of the 6 C-terminal modules (encoded by exons 59-63), but are associated with classic or severe phenotypes when found in cbEGF modules elsewhere in the gene.
AB - Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, a dominantly inherited disorder of connective tissue that primarily involves the cardiovascular, ocular, and skeletal systems. There is a remarkable degree of variability both within and between families with Marfan syndrome, and FBN1 mutations have also been found in a range of other related connective tissue disorders collectively termed type-1 fibrillinopathies. FBN1 mutations have been found in almost all of the 65 exons of the FBN1 gene and for the most part have been unique to one affected patient or family. Aside from the "hot spots" for the neonatal Marfan syndrome in exons 24-27 and 31-32, genotype-phenotype correlations have been slow to emerge. Here we present the results of temperature-gradient gel electrophoresis analysis of FBN1 exons 59-65. Six mutations were identified, only one of which had been previously reported. Two of the six mutations were found in patients with mild phenotypes. Taken together with other published reports, our results suggest that a sizable subset (ca. 40%) of mutations in this region is associated with mild phenotypes characterized by the lack of significant aortic pathology, compared with about 7% in the rest of the gene. In two cases, mutations affecting analogous positions within one of the 43 cbEGF modules of FBN1 are associated with mild phenotypes when found in one of the 6 C-terminal modules (encoded by exons 59-63), but are associated with classic or severe phenotypes when found in cbEGF modules elsewhere in the gene.
KW - Adolescent
KW - Adult
KW - Child
KW - Child, Preschool
KW - DNA Mutational Analysis
KW - Exons
KW - Female
KW - Fibrillin-1
KW - Fibrillins
KW - Genotype
KW - Humans
KW - Male
KW - Marfan Syndrome/genetics
KW - Microfilament Proteins/genetics
KW - Mutation
KW - Phenotype
KW - Polymerase Chain Reaction
KW - Protein Structure, Tertiary
U2 - 10.1002/(sici)1096-8628(20000320)91:3<212::aid-ajmg12>3.0.co;2-3
DO - 10.1002/(sici)1096-8628(20000320)91:3<212::aid-ajmg12>3.0.co;2-3
M3 - SCORING: Journal article
C2 - 10756346
VL - 91
SP - 212
EP - 221
IS - 3
ER -