Response to "Mutations of the NOGGIN and of the activin A type I receptor genes in fibrodysplasia ossificans progressiva (FOP)" by Lucotte et al.

by Lucotte et al. BY F.S. KAPLAN 1, M. XU, 2, G. FELDMAN 3, M. BROWN 4, T.-J. CHO 5, I.H. CHOI 5, J.M. CONNOR 6, P. LONGO RIBEIRO DELAI 7, A.N. ECONOMDES 8, D.L. GUSER 2, J. GROPPE 9, T. KATAGIRI 10, M. LE MERRER 11, R. MORHART 12, R. RAVAZZOLO 16, J.G. ROGERS 14, R. SMITH 15, J.T. TRIFFITT 16, J.A. URTIZBEREA 17, M. ZASLOFF 18 AND E.M. SHORE 5 We read with interest the recent letter by Lucotte et al. reporting mu- tations of the NOGGIN (NOG) and of the Activin A type I receptor (ACVRl) genes in fibrodysplasia ossificans progressiva (FOP; OMIM # 135100) (9). We recently mapped FOP to 2q23-24 by linkage analy- sis and identified an identical heterozygous missense activating muta- tion (c.617G>A;R206H) in the glycine-serine (GS) activation domain of ACVRl, a bone morphogenetic protein (BMP) type I receptor, in all classically-affected individuals tested with inherited and sporadic FOP from five continents (13). Previously, we excluded linkage between NOG and FOP in all classically-affected FOP families, and did not find TVOG disease-causing mutations in any classically-affected FOP patient in a large multinational study (15). We further showed that the reported NOG mutations of Lucotte et al. (lO)andSemonineia/. (11) were polymerase chain reaction (PCR) errors (15). In their most recent paper (9), the authors failed to mention or discuss the difference of opinion within the literature regarding the role of NOG in FOP (15). In addition, the authors did not indicate whether any of their reported mutations have been previously reported in the SNP databases. From the information provided in the paper, it is not clear what the mutation numbers correspond to in the 7VOG sequence, so it is impossible for an independent investigator to make this assessment. Any corresponding changes in amino acids are not reported. No support for functional changes (such as amino acid substitutions or nonsense mutations) is reported. The definitive identification of the FOP gene has recently been established (13). Although NOG is a very plausible candidate for FOP (1, 5, 8), the classic FOP phenotype is not linked to the NOG locus, nor has there been independent confirmation of disease-causing mutations in the protein-coding region of the NOG gene (15). Our extensive analysis and those of many other laboratories indicate that NOG mutations in FOP patients are in error (9, 15) and devoid of any potential functional consequences (6). Furthermore, Cohen, Carey, Xu, and Warman have indicated that some patients reported by Lucotte et al. may not have FOP (2, 3, 14, 16). More than five years ago, Carey invited Lucotte to present complete phenotypic data on all of his patients with reported NOG mutations and to share DNA samples with other laboratories outside of his consortium so that independent testing could occur (2). The invitation was unanswered. Recent identification of the specific mutation in ACVR1 that causes FOP has critical diagnostic and therapeutic implications for FOP (13), and has recently been validated in functional studies in silico (7), in vitro (4, 12), and in vivo (12). While mutations in NOG cause skeletal phenotypes in humans such as proximal symphalangism (SYM1; OMIM # 185800), multiple synostosis syndrome (SYNS1; OMIM # 186500), tarsal carpal coalition syndrome (TCC; OMIM # 186570) and brachydactyly type B2 (BDB2; OMIM # 611377), there is no plausible evidence that they cause FOP. REFERENCES 1. BROWN D.J., KIM T.B., PETTY E.M., DOWNS C.A., MARTIN D.M., STROUSE P.J., MOROI S.E., MLUNSKY J.M., LESPERANCE M.M.: Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in nog, the gene encoding noggin. Am. J. Hum. Genet., 2002, 71, 618-624. 2. CAREY J.C.: Editor's note. Am. J. Med. Genet., 2002, 109, 160. 3. COHEN M.M., Jr.: Bone morphogenetic proteins with some comments on fibrodysplasia ossificans progressiva and noggin. …