The pathogenicity of the Pro1148Ala substitution in the FBN1 gene: causing or predisposing to Marfan syndrome and aortic aneurysm, or clinically innocent? |
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Authors: | Iris Schrijver Wanguo Liu U Francke |
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Institution: | (1) Howard Hughes Medical Institute, Beckman Center, Stanford University Medical Center, Stanford, CA 94305-5428, USA Tel.: +1-415-725-8089; Fax: +1-415-725-8112; e-mail: francke@cmgm.stanford.edu, US;(2) Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA, US |
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Abstract: | In individuals with the Marfan syndrome (MFS), mutations have been identified in the fibrillin-1 gene (FBN1) at 15q21.1.
A proline-to-alanine change at position 1148 in exon 27 (Pro1148Ala) has been reported in probands with MFS, aortic aneurysm
or Marfanoid-craniosynostosis. It was suggested that this mutation could be a risk factor for aortic dilatation, since it
was rarely observed in control populations. To investigate further the pathogenicity of this substitution, we screened 416
unrelated control individuals by allele-specific oligonucleotide (ASO) hybridization. We found 16 individuals who carried
the alanine allele (3.8%), 3 of whom were homozygous. Five were of Latin American and eight were of Asian extraction. We also
screened 133 probands with MFS, aortic aneurysm or related connective tissue disorders and found 4 (3%) that were heterozygous
for the 1148Ala allele. All positive results were confirmed by DNA sequencing. In 20 individuals with 1148Ala, we confirmed
the association with the rarer A allele at the IVS27-5G→A polymorphism. Our results suggest that the Pro1148Ala change is
a polymorphism of ancient evolutionary origin that is more prevalent in Asian and Latin American than in Caucasian or African
populations.
Received: 4 October 1996 / Revised: 3 December 1996 |
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