A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome.

Abstract

Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBNJ allele and may define the phenotype associated with FBNI "null" alleles. (J. Clin.

The FBN1 (R2726W) mutation is not fully penetrant

“…In vitro experiments have demonstrated that Furin/PACE is unable to process profibrillin that has the R2726W mutation, and fibroblasts harbouring this mutation show markedly reduced deposition of fibrillin (Raghunath et al 1999). In vivo, impaired profibrillin processing caused by the R2726W mutation has been identified in one individual with isolated skeletal features of Marfan syndrome, and in six related subjects presenting with high stature (Milewicz et al 1995). This suggests that the availability of fibrillin for microfibrillogenesis is essential for correct skeletal development, and that MFS skeletal features or isolated high stature might develop in the absence of correct enzyme cleavage (Milewicz et al 1995).…”

“…This suggests that the availability of fibrillin for microfibrillogenesis is essential for correct skeletal development, and that MFS skeletal features or isolated high stature might develop in the absence of correct enzyme cleavage (Milewicz et al 1995). The proband in the study described above (Milewicz et al 1995) was a 13-yearold boy with isolated skeletal features of Marfan syndrome. He was six feet tall (183 cm, more than the 95th centile for his age) with an upper-to-lower segment ratio of 0.89 and with pectus carinatum, scoliosis, arachnodactyly, and pes planus.…”

“…To date, more than 500 mutations have been identified in this gene in patients with MFS and related diseases (Collod-Béroud & Boileau, 2002). The R2726W mutation in the FBN1 gene results in the substitution of tryptophan for arginine at nucleotide 8,176 (Milewicz et al 1995). Furin/PACE (paired basic aminoacid cleaving enzyme) is an endoprotease responsible for the proteolytic processing of proproteins to biologically active proteins.…”

“…In vivo, impaired profibrillin processing caused by the R2726W mutation has been identified in one individual with isolated skeletal features of Marfan syndrome, and in six related subjects presenting with high stature (Milewicz et al 1995). This suggests that the availability of fibrillin for microfibrillogenesis is essential for correct skeletal development, and that MFS skeletal features or isolated high stature might develop in the absence of correct enzyme cleavage (Milewicz et al 1995). The proband in the study described above (Milewicz et al 1995) was a 13-yearold boy with isolated skeletal features of Marfan syndrome.…”

Fibrillin expression and localization in various types of carcinomas of the thyroid gland

“…13 Moreover, a human fibrillin-1 mutation (Arg 2726 -Trp) which prevents proteolytic processing of the C-terminal domain, has been reported to result in impaired deposition of the product of the affected allele. 19 From a functional perspective, the possible role of fibrillin-1 localization in the neoplastic thyroid cells merits further investigation. The distribution of fibrillin-1 and fibrillin-2 in developing tissues suggests that both proteins are usually, but not exclusively, associated with elastic fibers.…”