Indian Journal of Dermatology
  Publication of IADVL, WB
  Official organ of AADV
Indexed with Science Citation Index (E) , Web of Science and PubMed
 
Users online: 5498  
Home About  Editorial Board  Current Issue Archives Online Early Coming Soon Guidelines Subscriptions  e-Alerts    Login  
    Small font sizeDefault font sizeIncrease font size Print this page Email this page


 
Table of Contents 
ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 355-358
Identification of Two Novel Frameshift Mutations of the ADAR1 Gene in Two Chinese Families With Dyschromatosis Symmetrica Hereditaria


From the Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China

Date of Web Publication2-Nov-2022

Correspondence Address:
Yanfei Zhang
157 Xi Wu Road, Xi'an 710004, Shaanxi Province
PR China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_207_21

Rights and Permissions

   Abstract 


Background: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant skin disease. The mutation of the ADAR1 gene is the pathogenesis of this disorder. Aims: This study aimed to identify the mutations of the ADAR1 gene in two Chinese families with DSH. Methods and Materials: Eight patients from two Chinese families were diagnosed with DSH clinically. Blood samples were collected from the patients and unaffected individuals. Sanger sequencing for all polymerase chain reaction products of the whole coding regions of the ADAR1 gene was performed to identify the mutations. Mutation Taster software was used to predict the impact of the variant on the resultant protein. Results: The c.3358-3359insT (p.L1053fs-1092X) mutation in exon 12 was found in affected members of the pedigree1. In pedigree2, the c.3820-3821insG (p.G1207fs-1213X) mutation in exon 15 was found. These two mutations were not found in 100 unrelated healthy people. In this study, both mutations were damaged by the Mutation Taster software. Conclusions: We identified two novel frameshift mutations in the ADAR1 gene. Our study expands the database of ADAR1 gene mutations in DSH.


Keywords: ADAR1 gene, dyschromatosis symmetrica hereditaria, genodermatose


How to cite this article:
Ning X, Xiao S, Zhang Y. Identification of Two Novel Frameshift Mutations of the ADAR1 Gene in Two Chinese Families With Dyschromatosis Symmetrica Hereditaria. Indian J Dermatol 2022;67:355-8

How to cite this URL:
Ning X, Xiao S, Zhang Y. Identification of Two Novel Frameshift Mutations of the ADAR1 Gene in Two Chinese Families With Dyschromatosis Symmetrica Hereditaria. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 4];67:355-8. Available from: https://www.e-ijd.org/text.asp?2022/67/4/355/360318





   Introduction Top


Dyschromatosis symmetrica hereditaria (DSH; Mendelian Inheritance in Man no. 127400) is sometimes called reticulate acropigmentation of Dohi.[1] It is an autosomal dominant skin disease with high penetrance, but some patients with sporadic DSH have been reported. It is thought to be a rare genodermatosis though the exact incidence of DSH is unknown. Because patients with DSH usually have only skin symptoms and some patients do not mind the skin lesions, it leads to underreporting.

DSH is characterized by mixed hyperpigmented and hypopigmented macules of various sizes on the dorsal side of the extremities, which usually appear in infancy or early childhood.[2] The symptoms always stop developing in puberty and last a lifetime. Sometimes the freckle-like pigmented macules can involve the face. There are no changes in color or distribution, once the lesions are fully established. The dermoscopic features of DSH include reticulate pigmented, hyperpigmented, or hypopigmented spots, diffuse pigmentation with hyperpigmented spots and monotonous pigmented or hypopigmented spots.[3]

The mutation of the ADAR1 gene (GenBank accession no. NM_001111.3, http://www.ncbi.nlm.nih.gov/genbank/) is the pathogenesis of this disorder.[4] The ADAR1 protein catalyses the transformation of adenosine to inosine in double-stranded RNA (dsRNA) substrates and is involved in various activities, such as viral inactivation, structural change of the protein and the resultant cell survival. However, its function in the skin and the mechanisms by which mutations in ADAR1 cause DSH are still mysterious. In this study, we performed a mutational analysis of the ADAR1 gene in two Chinese pedigrees with DSH.


   Subjects and Methods Top


Two pedigrees from the Shaanxi Province of China. This study was approved by the medical ethics committee of Xi'an Jiaotong University. After informed consent, 5 ml of peripheral blood samples were collected from the patients and unaffected individuals of the pedigree1 and pedigree2. Blood samples from 100 unrelated healthy Chinese population are considered as controls. Genomic DNA was extracted from peripheral blood lymphocytes by standard methods. The sequences of the primers were as previously described.[5] Sanger sequencing was applied to the mutation analysed. All 15 exons and the flanking intron sequences of ADAR1 were analysed by direct sequencing from polymerase chain reaction (PCR) amplicons. PCR was performed in 50 ul reaction volume containing 25 ng of genomic DNA, 0.3 mM dNTPs, 0.3 mM of each primer, 3.0 mM MgCL and 0.1 U of Taq DNA polymerase. The PCR conditions were as follows: Taq was activated at 95°C for 5 min, followed by 35 cycles, each cycle was denatured at 95°C for 30 s, annealed at 56°C for 60 s and extended at 72°C or 2 min, and the final extension was 72°C for 5 min. After amplification, the products were purified using a QIAquick PCR Purification Kit (Qiagen). We sequenced the ADAR1 gene using ABI PRISM 3730 automated sequencer (Applied Biosystems). Sequence comparisons and analysis were performed by the Phred-Phrap-Consed Version 12.0 program. Mutation Taster software (https://www.mutationtaster.org) was used to predict the impact of the variant on the resultant protein.


   Results Top


As shown in [Figure 1], pedigree 1 consists of two affected and one unaffected individuals, the proband was a 6-year-old boy. He was born with hyperpigmented and hypopigmented macules on the extensor aspect of his fingers and toes and then extended to the dorsal aspect of his hands and feet. Freckles appeared on his face when he was 2 years old. These lesions were irregular in shape and size and asymptomatic. His father also had the same clinical manifestations in his childhood. The skin lesions became more pronounced after exposure to sunlight. Pedigree 2 includes 6 affected and 16 unaffected individuals. The proband was a 12-year-old girl. He had asymptomatic hyperpigmented and hypopigmented macules on the back of the hands and feet at the age of 2 years and then gradually became prominent. The skin lesions became more pronounced when exposed to the sun. Other affected individuals in the pedigree2 showed similar skin changes. All the characteristics support the diagnosis of DSH in clinical.
Figure 1: DSH pedigrees of the two families. (a) Pedigree of family 1 and (b) Pedigree of family 2. Affected members are represented by black symbols. The proband is indicated by the arrow

Click here to view


The results of the sequence analysis are shown in [Figure 2]. A frameshift mutation c.3358-3359insT (p.L1053fs-1092X) in exon 12 was found in the proband and his affected father of the pedigrees1, but not found in healthy individuals or the 100 unrelated controls. The T insert caused a frameshift mutation with the change of amino acids from 1053 to 1091 and introduced a new terminating TGA codon at position 1092. In pedigrees2, a frameshift mutation c.3820-3821insG (p.G1207fs-1213X) in exon 15 was found in patients and other affected individuals, but not found in healthy members. The G insert caused a frameshift mutation with the change of amino acids from 1207 to 1212 and introduced a new terminating TAG codon at position 1213. This mutation was not found in 100 unrelated controls. All these mutations were not included in the NCBI SNP database and it is suggested that the novel mutations may be a pathological mutation of DSH. Both these mutations in this study were damaged by the Mutation Taster software.
Figure 2: Mutations of the ADAR1 gene in two families. (a) c.3358-3359insT mutation in exon 12 of the ADAR1 gene in the proband of family 1. (b) Wild-type allele of exon 12 of the ADAR1 gene. (c) c.3820-3821insG mutation in exon 15 of the ADAR1 gene in the proband of family 2. (d) Wild-type allele of exon 15 of the ADAR1 gene

Click here to view



   Discussion Top


DSH is a rare autosomal dominant pigmentary genodermatosis, but it has been reported to be transmitted in an autosomal recessive form. DSH mainly occurs in East Asian countries, such as Japan, China (including Taiwan) and Korea, with a few cases described among Indians, Europeans and South Americans. It reported that 77.6% of patients had a family history and 22.4% with no family history. Besides skin lesions, it may be accompanied by other diseases, such as bilateral striatal necrosis, chilblains, congenital heart disease and hemangioma disease.[6],[7],[8]

Clinically, it is not difficult to diagnose DSH, but it always needs to be differentiated from other hereditary pigmentary disorders. The hyperpigmented and hypopigmented macules of dyschromatosis universalis hereditaria (DUH) present are distributed all over the body, about half of the patients with freckle-like pigmentation on face, and the lesions do not change with seasons.

The rash characteristics of DUH are similar to DSH, but no ADAR1 mutations have been identified in patients with DUH, indicating that these two entities are genetically distinct.[9] Research findings showed that ABCB6 mutations may be the pathogenic gene associated with DUH.[10]

Reticularis Acropigmentatio Kitamura (RAK) presents as reticular pigmentation on the dorsa of hands and feet. The difference with DSH is that RAK has no depigmentation lesions, and reticular pigmentation is slightly concave and atrophy. Whole-exome sequencing-identified ADAM10 gene mutations was the pathogenesis of RAK.[11]

Xeroderma pigmentosum (XP) is another condition in the differential diagnosis of DSH. The difference between XP and DSH lies in that XP-present freckle-like lesions, which occur mainly in sun exposure sites, xerosis, symptoms of keratin, development of skin tumors (mostly basal cell carcinoma and squamous cell carcinoma) before the age of 20, and 80% of the patients with the damage of eyes. Many patients are mentally retarded and have poor development. The conditions are also genetically distinct.

Sometimes DSH should be differentiated from vitiligo. Vitiligo is distinguished from DSH by the development of sharply demarcated milky depigmented macules, which occur in any part of the body and are always the response to treatment.

There is no etiologic treatment in the clinic, but the combination of miniature punch grafting and excimer light to treat hypopigmented macules showed effectively.[12] For lesions on the exposed area, sun-protective clothing, umbrellas and sunscreen lotions are effective to some extent.[13]

ADAR1 gene is the pathogenesis of this disorder.[4] However, no mutations of the ADAR1 gene have been detected in some DSH families. There may be other genes involved in this disease. ADAR1 was located on chromosome 1q11-q12 and identified as the gene responsible for DSH.[4],[14] ADAR1 spans up to 40 kb, contains 15 exons and consists of 1226 amino acid residues. It has two Zalpha (Z-DNA-binding domain in adenosine Deaminases in the N-terminal region), three DSRM (double-stranded RNA binding motif) and one ADEAMc domain in the C-terminal region, corresponding to exon 2, exons 2–7 and exons 9–15, respectively.[15] Including our two new mutations, more than 60% of the mutations are located in the ADEAMc domain, so it is believed that the mutations within the ADEAMc domain play an important role in the onset of DSH, and this domain may be the hot spot for ADAR1 mutations, but further research is needed.

In this study, we detected two mutations, c.3358-3359insT (p.L1053fs-1092X) in exon 12 and c.3820-3821insG (p.G1207fs-1213X) in exon 15. These two mutations lead to frameshift and premature translation termination, making the truncated protein with no dsRNA-binding domains and deaminase catalytic domain. But still, there is a need to detect the ADAR1 protein expression in the future to support this speculation. The function of ADAR1 in the development of DSH is still unknown. Recent studies show that the ADAR1 p150 isoform is the determinant of DSH, and 5'UTR c.-60A>G variant of ADAR1 may lead to DSH.[16],[17] But it still remains unknown why all these different mutations and different mutation styles could cause the same phenotype and why the same mutation can lead to different phenotypes.

This study expands the database of ADAR1 gene mutations in DSH. More findings of novel mutations will help to further clarify the pathogenesis, reveal the correlation between phenotypes and genotypes of DSH and then provide more information on genetic counselling and molecular testing for the child-bearing couple. Further investigations should focus on the potential signaling pathway.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by National Natural Science Foundation of China (No. 81703129).

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Ostlere LS, Ratnavel RC, Lawlor F, Black MM, Griffiths WA. Reticulate acropigmentation of Dohi. Clin Exp Dermatol 1995;20:477-9.  Back to cited text no. 1
    
2.
Li M, Jiang YX, Liu JB, Yang S, He PP, Gao M, et al. A novel mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. Clin Exp Dermatol 2004;29:533-5.  Back to cited text no. 2
    
3.
Chi C, Luo Y, Liu J. A novel frameshift mutation of the ADAR1 gene in a Chinese patient with dyschromatosis symmetrica hereditaria and the dermoscopic features. J Eur Acad Dermatol Venereol 2017;31:e484-5.  Back to cited text no. 3
    
4.
Miyamura Y, Suzuki T, Kono M, Inagaki K, Ito S, Suzuki N, et al. Mutations of RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 2003;73:693-9.  Back to cited text no. 4
    
5.
Li M, Li C, Hua H, Zhu W, Lu Y, Yang L. Identification of two novel mutations in Chinese patients with dyschromatosis symmetrica hereditaria. Arch Dermatol Res 2005;297:196-200.  Back to cited text no. 5
    
6.
Kono M, Suganuma M, Dutta A, Ghosh SK, Takeichi T, Muro Y, et al. Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression. Br J Dermatol 2018;179:509-11.  Back to cited text no. 6
    
7.
Kono M, Suganuma M, Shimada T, Ishikura Y, Watanabe S, Takeichi T, et al. Dyschromatosis symmetrica hereditaria with chilblains due to a novel two-amino-acid deletion in the double-stranded RNA-binding domain of ADAR1. J Eur Acad Dermatol Venereol. 2018;32:e394-6.  Back to cited text no. 7
    
8.
Zhou Q, Zhang L, Zhang Y, Luo H, Zhu L, Wang P, et al. Two novel ADAR1 gene mutations in two patients with dyschromatosis symmetrical hereditaria from birth. Mol Med Rep 2017;15:3715-8.  Back to cited text no. 8
    
9.
Suzuki N, Suzuki T, Inagaki K, Ito S, Kono M, Fukai K, et al. Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis. J Invest Dermatol 2005;124:1186-92.  Back to cited text no. 9
    
10.
Zhang C, Li D, Zhang J, Chen X, Huang M, Archacki S, et al. Mutations in ABCB6 cause dyschromatosis universalis hereditaria. J Invest Dermatol 2013;133:2221-8.  Back to cited text no. 10
    
11.
Kono M, Sugiura K, Suganuma M, Hayashi M, Takama H, Suzuki T, et al. Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease. Hum Mol Genet 2013;22:524-33.  Back to cited text no. 11
    
12.
Kawakami T, Otaguchi R, Kyoya M, Soma Y, Suzuki T. Patient with dyschromatosis symmetrica hereditaria treated with miniature punch grafting followed by exciner light therapy. J Dermatol 2013;40:771-2.  Back to cited text no. 12
    
13.
Kono M, Okamoto T, Takeichi T, Muro Y, Akiyama M. Dyschromatosis symmetrica hereditaria may be successfully controlled by topical sunscreen. Eur J Dermatol 2018;28:840-1.  Back to cited text no. 13
    
14.
Zhang XJ, Gao M, Li M, Li M, Li CR, Cui Y, et al. Identification of a locus for dyschromatosis symmetrica hereditaria at chromosome 1q11-1q21. J Invest Dermatol 2003;120:776-80.  Back to cited text no. 14
    
15.
Schade M, Turner CJ, Kühne R, Schmieder P, Lowenhaupt K, Herbert A, et al. The solution structure of the Z-alpha domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA. Proc Natl Acad Sci USA 1999;96:12465-70.  Back to cited text no. 15
    
16.
Zhang JY, Chen XD, Zhang Z, Wang HL, Guo L, Liu Y, et al. The adenosine deaminase acting on RNA 1 p150 isoform is involved in the pathogenesis of dyschromatosis symmetrica hereditaria. Br J Dermatol 2013;169:637-44.  Back to cited text no. 16
    
17.
Suganuma M, Kono M, Yamanaka M, Akiyama M. Pathogenesis of a variant in the 5' untranslated region of ADAR1 in dyschromatosis symmetrica hereditaria. Pigment Cell Melanoma Res 2020;33:591-600.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2]



 

Top
Print this article  Email this article
 
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (730 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Subjects and Methods
   Results
   Discussion
    References
    Article Figures

 Article Access Statistics
    Viewed236    
    Printed6    
    Emailed0    
    PDF Downloaded12    
    Comments [Add]    

Recommend this journal