Novel Mutations in ACVR1 Result in Atypical Features in Two Fibrodysplasia Ossificans Progressiva Patients

Kirsten A Petrie,Jenny J Pointon,Alex N Bullock,Matthew A Brown,Roger Smith,James T Triffitt,B Paul Wordsworth,R Graham G Russell,Wen Hwa Lee,David C Rubinsztein

doi:10.1371/journal.pone.0005005

Abstract

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, heritable condition typified by progression of extensive ossification within skeletal muscle, ligament and tendon together with defects in skeletal development. The condition is easily diagnosed by the presence of shortened great toes and there is severe advancement of disability with age. FOP has been shown to result from a point mutation (c.617G>A) in the ACVR1 gene in almost all patients reported. Very recently two other mutations have been described in three FOP patients. We present here evidence for two further unique mutations (c.605G>T and c.983G>A) in this gene in two FOP patients with some atypical digit abnormalities and other clinical features. The observation of disparate missense mutations mapped to the GS and kinase domains of the protein supports the disease model of mild kinase activation and provides a potential rationale for phenotypic variation.

Highlights

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant disease with complete penetrance involving the progressive ossification of the skeletal muscles, fasciae, tendons and ligaments
Individuals with FOP appear normal at birth except for great toe abnormalities; these being short, deviated and later monophalangic
Minor trauma or viral illnesses can initiate acute inflammatory mysositic episodes leading to progressive heterotopic ossification, which is amplified by surgical intervention or removal

Summary

Introduction

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant disease with complete penetrance involving the progressive ossification of the skeletal muscles, fasciae, tendons and ligaments. This nonsynonymous mutation causes an Arg206His amino acid substitution within the GS (glycine-serine rich) domain of the ACVR1 protein, and has been confirmed by our further work and by others [6,7]. The switch between the inactive and active states has been illustrated by crystal structures of the type I TGF-beta receptor kinase domain as well as its complex with FKBP12 [9,10].

Results

Conclusion