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Year : 2016  |  Volume : 82  |  Issue : 3  |  Page : 306-307

Misinterpretation of ATP2C1 gene mutations

Massimo Micaroni 
 School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, China

Correspondence Address:
Prof. Massimo Micaroni
School of Pharmaceutical Science and Technology, Dalian University of Technology, West Campus, No. 2 Linggong Road, Dalian 116024

How to cite this article:
Micaroni M. Misinterpretation of ATP2C1 gene mutations.Indian J Dermatol Venereol Leprol 2016;82:306-307

How to cite this URL:
Micaroni M. Misinterpretation of ATP2C1 gene mutations. Indian J Dermatol Venereol Leprol [serial online] 2016 [cited 2020 May 27 ];82:306-307
Available from: http://www.ijdvl.com/text.asp?2016/82/3/306/175922

Full Text


I have carefully read the manuscript of Tian et al., where the authors reported several mutations of the human ATP2C1 gene, six of which they claim to have been identified for the first time.[1] However, two of them have been reported previously.

Tian et al. reported as new “the aberrant splice mutation c.621 (-1A>G) in exon 3 of the ATP2C1 gene from the patient FHHD-3”.[1] However, the authors did not indicate any gene to properly address the reported mutation making proper localization of the reported mutation along the ATP2C1 gene difficult. Nevertheless, the coding region surrounding the mutation as reported in [Figure 1]e of Tian et al.[1] (TCT AAT AAG CTG ATC T; underlined is the mutated site), overlaps with the intron 2/exon 3 region of the ATP2C1 gene as reported previously by Sudbrak et al. [Table 1].[1],[2] Moreover, in a previous report, Fairclough et al. described a mutation (patient NC12, mutation 118 [−1G>A], aberrant splicing in intron 2) that is identical to that reported to be new by Tian et al. (patient FHHD-3, mutation 621 [−1A>G] aberrant splicing in exon 3).[1],[3]

In addition, two further mistakes may also be noticed in Tian et al's. paper.[1] First, the mutation reported by Tian et al. would be a single nucleotide substitution A>G on the last nucleotide of intron 2 and not of exon 3 as reported by Tian et al.[1] [see also [Table 1] in Fairclough et al.].[3] Second, the adenine at position-1 of the splice site of intron 2/exon 3 is present in the mutated sequence of the ATP2C1 gene, whereas guanine is in the original position and not vice versa as reported by Tian et al.[1],[2],[3] Thus, the mutation reported in the ATP2C1 gene in patient FHHD-3 is not new and has not been correctly reported (neither for corresponding nucleotide position (118, and not 621) nor nucleotide replacement [G>A and not A>G, is the correct mutation]).

Further analysis of the manuscript indicated some more inconsistencies. Tian et al. referring to the patient SHHD-5 described a new missense c. 666T>C in exon 3, generating a glycine in the place of arginine [R66G].[1] However, while glycine is coded by four codons (GGT, GGC, GGA, and GGG), the arginine is coded by six codons (CGT, CGC, CGA, CGG, AGA, and AGG). Therefore, what has been reported by Tian et al. may not be correct.[1] Besides, according to the reported mutation, if thymine was replaced with cytosine in the unique codon encoding for an arginine containing a thymine (CGT), one generates CGC which is still coding for an arginine. However, something interesting comes up if the correct reading frame of the ATP2C1 is considered [see [Table 1] in Sudbrak et al.].[2] The surrounding sequence of the ATP2C1 gene where the mutation c. 666T>C in patient SHHD-5 occurs [Figure 1]g in Tian et al.], presents the reading codon frame CAT AGG CGA GCC TTT (encoding for His-Arg-Arg-Ala-Phe, respectively; underlined is the mutation site).[1] First, the codon CGA, where the mutation is located, is codon 55 and not codon 66, as reported by Tian et al. (for the correct coding sequence, relative frame and corresponding amino acid sequence, see http://www.ncbi.nlm.nih.gov/nuccore/AF181120).[1] Second, in the mutation c. 666T>C, cytosine was replaced with thymine (and not 666T>C - which would have meant that thymine was replaced with a cytosine), which whould generate a TGA codon which is a STOP codon. The codon CGA could be mutated encoding for a glycine replacing thymine with cytosine. Furthermore, this mutation has been previously described.[4] Interestingly, the same team of authors of the manuscript reported this mutation in exon 13 instead of exon 3 (patient FHHD-8, c. 163C>T), indicating it as “recurrent” [Table 1].[1],[5]


I would like to thank Prof. Gary Xiao, Dalian University of Technology, Dalian, China, for supporting my research. Thanks to Dr. Seetharaman Parashuraman, TIGEM Institute, Naples, Italy and to Dr. Giuseppe Perinetti, University of Trieste, Italy, for critical reading of the manuscript.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Tian H, Chen M, You J, Fu X, Liu H, Shi Z, et al. Six novel mutations of ATP2C1 identified in eight Chinese patients with Hailey-Hailey disease. Indian J Dermatol Venereol Leprol 2013;79:245-7.
2Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J, White J, et al. Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca (2) pump. Hum Mol Genet 2000;9:1131-40.
3Fairclough RJ, Lonie L, Van Baelen K, Haftek M, Munro CS, Burge SM, et al. Hailey-Hailey disease: Identification of novel mutations in ATP2C1 and effect of missense mutation A528P on protein expression levels. J Invest Dermatol 2004;123:67-71.
4Zhang GL, Sun YT, Shi HJ, Gu Y, Shao MH, Du XF. Mutation analysis of ATP2C1 gene in a Chinese family with Hailey-Hailey disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2010;27:414-6.
5Zhang HZ, Tian HQ, Du DH, Wang GJ, Yan XX, Liu H, et al. Analysis of ATP2C1 gene mutations in Chinese patients with Hailey-Hailey disease. Clin Exp Dermatol 2012;37:190-3.


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