Acro-Osteolysis and Symphalangism Mutations

Authors


We read with great interest the report by Tanikawa et al.(1) published in the January issue of JBMR. In this report, the authors describe the unusual combination of adult-onset idiopathic progressive acro-osteolysis with proximal symphalangism. The authors report the identification of six different mutations in NOG in the described patient. In our opinion, this observation raises two important methodological issues. First, it is unclear which reference sequence the authors used to determine the presence of mutations in the NOG gene. When using the published consensus sequence of NOG (NCBI Reference Sequence NM_005450) and the current recommendations for mutation nomenclature (available at http://www.genomic.unimelb.edu.au/mdi/mutnomen/), only three of the reported sequence alterations (176 A > T, 203 C > G, and 208 C > G) are theoretically possible. Assuming that nucleotide 1 is the A of the ATG translation initiation codon, we noticed that, at positions 14, 173, and 180, the consensus sequence differs from the bases given by the authors (Table 1). The authors also do not specify what the consequences of the DNA alterations are on the amino acid level, and they do not exclude the possibility that the sequence alterations are polymorphisms. Thus, it remains questionable whether the reported sequence alterations are indeed true mutations with functional consequences. Second, the presence of multiple disease-causing mutations within one gene in the same patient is unusual. The question is whether the sequence alterations represent PCR-induced artifacts or not. In the past, there has already been some debate concerning the presence of NOG mutations in patients with fibrodysplasia ossificans progressiva.(2-4) Mutations in these patients were identified using a nested PCR reaction, and this increases the likelihood for PCR-induced artifacts. It would be very interesting to know which method the authors used to screen the NOG gene for mutations and how they confirmed the presence of the mutations in an independent matter.

Table Table 1.. Comparison of the Bases at the Different Positions Using the Complete NOG Sequence (NM_005450) as a Reference
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In summary, we believe that further analyses are required to confirm the presence of NOG mutations in this patient.

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