We appreciate the comments of He et al.1 Our response is outlined below.
In fact, it had been reported that HSD17B10 is a part of a multigene domain in Xp11.21–p11.22 that escapes X-inactivation.2 Later results by Carrel et al3 showed that this gene is probably subjected to X-inactivation as only one of nine hybrids escapes from it. This observation can not be inferred from Figure 2 of Yang et al,4 while the results are more clarifying in the adapted figure of the letter of He et al.1
To elucidate whether HSD17B10 cDNA doses differed between both sexes, we performed relative quantification (RQ) of wild-type HSD17B10 cDNA alleles in four female and four male controls. The results did not show any significant difference between the doses in both sexes. Therefore, these results are in favour of an X-linked disease that does not escape X-inactivation and are in agreement with the observations of Carrel et al.3
Fibroblasts were obtained from a single biopsy, as it would not have been ethical to perform additional biopsies with the only purpose of performing these studies. In fibroblasts we not only performed genetic studies but also determined enzymatic activities with good correlation between both, which gives more strength to the results.
Relatively large deviations are often observed in real-time PCR quantification, owing to the low specificity of the probes and variability of the endogenous controls. However, despite these difficulties, the same expression levels in the first female patient and her brother were observed, which is in agreement with the sequencing results, the low enzymatic activity, the severe clinical presentation and the skewed X-inactivation pattern. The second female showed expression of both mutant and wild-type alleles, which is also in agreement with sequencing results, normal enzymatic activity, slight clinical presentation and random X-inactivation pattern.
In conclusion, our results are adequately supported by the studies in controls and are confirmed by the studies in patients.
We thank He et al for giving us the opportunity to clarify some issues, although we think that they do not change the conclusions of our study.
References
He X-Y, Dobkin C, Yang S-Y : Does the HSD17B10 gene escape from X-inactivation? Eur J Hum Genet 2011; 19: 123–124.
Miller AP, Willard HF : Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation. Genetics 1998; 95: 8709–8714.
Carrel L, Willard HF : X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434: 400–404.
Yang SY, He XY, Miller D : Gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids. Mol Genet Metab 2007; 92: 36–42.
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García-Villoria, J., Gort, L., Madrigal, I. et al. Reply to He et al. Eur J Hum Genet 19, 124 (2011). https://doi.org/10.1038/ejhg.2010.194
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DOI: https://doi.org/10.1038/ejhg.2010.194
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