A novel FBN1 mutation in a Chinese family with isolated ectopia lentis

• Introduction
• Methods
• Results
• Discussion

Abstract

Purpose: To identify the genetic defect in an autosomal dominant isolated ectopia lentis (EL) family.

Methods: Detailed family history and clinical data were collected from the family including sixteen patients with isolated EL. Blood samples of nine patients, one normal person and two unknown children’s were collected. Genomic DNA was extracted from leukocytes of peripheral blood. Genotyping was performed by microsatellite markers and logarithm-of-odds (LOD) scores were calculated using the LINKAGE Programs. Mutation screening in the candidate gene, fibrillin-1 (FBN1), was performed by direct sequencing.

Results: Linkage to the FBN1 locus is verified. Mutation screening in FBN1 identified a C>T transition at nucleotide position c.2920. This nucleotide change results in the cysteine substitution for highly conserved arginine at codon 974 (p.R974C). This mutation is identified in all affected individuals but is not found in 50 control healthy people.

Conclusions: A novel mutation of FBN1 results in an arginine to cysteine residue (p.R974C) substitution, which is responsible for the patients with isolated EL in this Chinese family.

Ectopia lentis (EL) is an inherited connective disorder characterized by lens dislocation. Most cases of EL are associated with Marfan syndrome, a genetic autosomal dominant disorder that is characterized by manifestations involving the cardiovascular, skeletal, and ocular systems [1].

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15q have been described in patients with classical Marfan syndrome, neonatal MFS, aortic aneurysms, ectopia lentis, Marfanoid skeletal features, familial arachnodactyly, Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome, and severe progressive kyphoscoliosis [2-6].

An isolated EL pedigree has been reported several times in different races [7-10]. This kind of phenotype may be an independent subtype caused by specific FBN1 mutations and other regulatory factors.

In this study, we recruited a Chinese family affected with isolated EL. Linkage to the FBN1 locus is identified. Mutation screening in FBN1 identified a C>T transition at nucleotide position c.2920. This nucleotide change results in the substitution of highly conserved arginine by cysteine at codon 974 (p.R974C). The mutation is cosegregated in the patients but not found in the 50 control subjects from the same ethnic background.

In the present study, we identified a novel mutation (R974C) in FBN1 from a Chinese family with isolated EL. This missense variation is found in all the affected family members. The mutation leads to a cysteine substitution for highly conserved arginine in the 8-Cys repeat latent transforming growth factor-beta binding protein (LTBP) motif encoded by FBN1 exon 25.

To date, over 600 mutations in FBN1 have been reported. The relationship between the genotype and the phenotype is still not clear [12]. Some information is concluded from reported materials by researchers [13]. For instance, mutations in exons 24–32 of FBN1 are usually associated with a severe form of Marfan syndrome (MFS), called neonatal MFS [13]. Mutations of cysteine substitution are usually associated with isolated EL [14]. On the another hand, some facts obstruct the conclusion, including mutations in the exons 24–32 of FBN1 caused MFS and isolated EL, and the same mutation can cause MFS and isolated EL in different families. Since these conclusions were obtained from the clinical materials, but not from the pathogenic mechanism, we can not correlate the genotype and the phenotype from clinical symptoms only. So, we need to explain the pathogenic mechanism on the molecular biologic level.

Fibrillin-1 is a large (320 kDa) multidomain glycoprotein that is a main component of the 10 to 12 nm sized extracellular microfibrils found in a wide range of tissues. Fibrillin-1 is considered to be important for elastogenesis, elasticity, and homeostasis of elastic fibers [15,16].

In the previous experiments, researchers found that fibrillin-1 was not only a structural component of extracellular matrix but also was a mediator of the transforming growth factor-beta (TGFβ) signaling pathway [17,18]. Mutations that influence the TGFβ signaling pathway are believed to cause severe multiple defects [19].

Through a literature search, eighteen mutations of FBN1 causing EL were found [8-10,14,20-23]. In these mutations, three mutations of FBN1 can cause EL and MFS in different families. Mutations of cysteine substitution were found in fifteen families [8-10].

In this study, we found the extra created cysteine in the LTBP motif only results in isolated EL. This suggests that the correct cysteine localization and disulfide binding play an important role in the structural integrity of the lens suspensory ligaments. The change has no or slight effect in the extracellular matrix of other organs.

It is reported that some specified mutation can cause MFS and isolated EL in different families. This may be influenced by genetic or environmental modifiers.

In summary, we report a novel conserved arginine to cysteine substitution in exon 25 of FBN1 which is associated with isolated EL. Our results further expanded the mutation spectrum of FBN1 and provided useful materials to the further researches.