Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome

Abstract

Mutations in the gene coding for fibrillin on chromosome 15 (FBN1) are known to cause Marfan syndrome (MFS). A related disorder, dominant ectopia lentis (EL), has also been linked genetically to this locus. We now describe ten novel mutations of FBN1 resulting in strikingly different phenotypes. In addition to classic MFS, FBN1 mutations also give rise to EL and a severe neonatal form of MFS. Interestingly, the neonatal MFS mutations are clustered in one particular region of FBN1, possibly providing new insights into genotype-phenotype comparisons.

Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype–phenotype correlations in FBN1 exons 24–40

“…One may speculate that T1020A could cause a similar, but less pronounced, disturbance of interdomain flexibility. Together with the mutation K1023N, reported in a patient with nMFS, 21 a total of three unique mutations have been reported in the interdomain region between LTBP no. 3 and cbEGF no.…”

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

“…Other fibrillinopathies FBN1 mutations were also found in incomplete forms of MFS as well as in several other MFS-related disorders such as nMFS, isolated ectopia lentis, ShprintzenGoldberg craniosynostosis syndrome (SGS), familial thoracic aortic aneurysms and dissections (TAAD), and autosomal dominant Weill-Marchesani syndrome (Table 1) (Faivre et al 2003;Francke et al 1995;Kainulainen et al 1994;Milewicz et al 1996;Sood et al 1996). This resulted in the recognition of ''fibrillinopathies'' caused by FBN1 aberrations (Charbonneau et al 2004).…”

An accurate method for comparing transcript levels of two alleles or highly homologous genes: application to fibrillin transcripts in Marfan patients' fibroblasts.

“…To compare the steady-state mRNA levels of T649 ~ G W217G 6 2 G3o69 --~ C K1024N 24 3 G --~ T in the fifth position of intron 25 --~ deletion of exon 25 (A25) 4 A3128 -~ G K1043R 25 5 deletion of A3191 -~ stop after 25 amino acid 1087 in exon 26 6 T322o --~ C C1074R 26 7 A3391 --~ T N1131Y 27 8 C341o --~ G R1137P 27 9 T4s37 --) C C1513R 36 10 C64s3 --~ G C2151W 52 11 G7879 ---) A G2627R 63 12 G8268 ~ A W256 stop 65 1 3 c T649 ~ G W21 7G + G2627R 6, 63 G7879 --> A Kainulainen et al (1994) Kainulainen et al (1994) Wang et al (1996) Wang et al (1996 the two FBN1 alleles in 13 patients with a known FBN1 mutation (Table 1), total RNA isolated from cultured fibroblasts was reverse transcribed and amplified by PCR. The corresponding RNA samples without a preceding reverse transcription step were amplified; analysis of these samples showed no genomic contamination.…”