Little has been reported about this phenotype in Chinese family. Thus,

in addition to hallmarks of ‘classical’ SPD, the phenotype displayed by individuals carrying the G220A mutation presents also additional features, such as the fifth finger clinodactyly, that are Selumetinib mw not always associated with canonical SPD in Chinese family. A number of different mutations in the HOXD13 gene have been shown to cause SPD in human. These include various degrees of polyalanine expansions, which cause ‘classical’ SPD [20] and [21], and frameshifting deletions, which are predicted to result in non-functional truncated proteins, lacking the homeodomain, that cause atypical forms of SPD [22]. Most of the mutations were located in the homeodomain of HOXD13, and little is known about the regions outside the homeodomain [23]. As in the case of many HOX proteins, the regions other than the homeodomain are poorly characterized as to their function. This mutation found in this family caused a c.659G>C transition in exon 1 of HOXD13, resulting in the p.Gly220Ala change. The G220A mutation represents the substitution of a

structurally versatile amino acid (glycine) with a hydrophobic amino acid (alanine). The introduction of a hydrophobic amino acid in a protein is likely to produce structural alterations, leading to the exposure of regions that are see more buried in the native state, thus possibly causing aggregation and the subsequent degradation of the protein [24]. Also this residue is highly conserved among different species Etomidate (Fig. 1). The high evolutionary conservation of this glycine residue indicates that it may play a relevant structural role within a functional domain of the HOXD13 protein. As previously reported, a large region of the HOXD13 protein N-terminal to the homeodomain can be divided into

two portions that retain transcriptional activation capability. Residue 220 lies in one of these regions, which spans amino acids 131–267 [23]. The c.659G>C (p.Gly220Ala) mutant showed less reduced transcription activation ability compared with c.940A>C (p.Ile314Leu), which could partly explain the mild phonotype of this family. In our data, the c.940A>C (p.Ile314Leu) mutant showed 22% reduced transcription activation ability compared with the wild type, which was concurrent with a previous report [9]. This result suggested that our assay was valid. A G220V missense mutation in HOXD13 was reported by Fantini et al. for a Greek family with SPD, which caused different phenotypes from the one reported here [23]. In Greek family, the proband showed webbing of the 3/4 fingers, clinodactyly of the right fifth finger and camptodactyly of the left fifth finger. No finger webbing was found in his left hand. The main malformation in our family was the bilateral syndactyly of the 3/4 fingers and bilateral fifth finger clinodactyly.