Thus, according to our data and published data, this missense substitution could be classi- fied as a high-probability pathogenic variant. Moreover, it was not found in any of the public SNP databases or in 340 control chromosomes. p.N125S occurs in a moderately conserved site in the multisequence alignment (Figure 1D) and in a conserved functional domain (ANK1) it is a nontolerated change affecting protein function with a score of 0.01 by the SIFT program ( /sift/SIFT.html) and is predicted to be “probably damaging” by the PolyPhen program ((11). This substitution was previously described in a 42-year-old woman with adult-onset FSGS by Santín et al. It results in an asparagine-to-serine substitution (p.N125S) within the first ankyrin repeat (ANK1) of the TRPC6 protein (Figure 1A). The missense mutation c.374A Ͼ G was found in two siblings (18-PG and 19-PR Table 1) with early-onset NS at the ages of 4 and 14 years, respectively. , P15S and A404V ) with an amino acid change were found in 11 pa- tients, whereas a few others (p.N561N, p.F843F, p.T714T, and p.Q904Q) that did not result in an amino acid change were finally detected in a significant portion of our patient cohort ( n ϭ 15). A few additional innocuous single-nucleotide polymor- phisms (SNPs i.e. were identified in two sporadic patients and in two siblings (5-RB, 13-MS, 18-PG, 19-PR) with NS in early ( n ϭ 2) or late ( n ϭ 2) childhood (Table 1).
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