A Novel Small Deletion in the ATP2A2 Gene in a Patient with Sporadic Darier’s Di

时间：2024-09-03

Chong Wang, Jing Luan, Zhen-Min Niu, Qiong Huang, Zheng-Hua Zhang,∗

1Department of Dermatology, Liaocheng People’s Hospital, Liaocheng, Shandong 252000, China, 2Department of Dermatology,Huashan Hospital, Fudan University, Shanghai 200040, China, 3MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI), Shanghai 200040, China.

Abstract

Keywords: Darier’s disease, neuropsychiatric features, ATP2A2, case report

Introduction

Darier’s disease(DD;OMIM:124200)is a rare autosomal dominant genodermatosis characterized by red-brown keratotic papules mainly in seborrhoeic areas and comorbid with psychiatric illnesses. The causal gene for DD is ATP2A2(OMIM:108740)on chromosome 12q23-q24.1, which encodes an endoplasmic reticulum calcium pump called SERCA2. The ATP2A2 gene is widely expressed in the brain, and calcium is one of the most important intracellular messengers in the human brain,which suggests that the high prevalence of comorbid psychiatric illnesses in DD is not simply due to the patient’s psychological reaction to severe and chronic skin symptoms. Herein, we report the sporadic case of a patient with severe DD and depression, and identified a novel mutation c.2993_2994del (p. Val998Alafs∗33).

Case report

A 29-year-old man presented with a 15-year history of brown, harsh keratotic papules on his scalp, face, neck,trunk,axillae,inguinal region,and upper limbs(Fig.1A).The lesions gradually coalesced into verrucous plaques,and were exacerbated in summer.No nail or oral mucosal changes were observed. There was no family history of skin disease. Although he had experienced persistent depression since his illness began, he had previously refused to undergo DNA testing in order to avoid either of his parents being blamed for his condition. Histological examination of a biopsy specimen obtained from his waist revealed suprabasal cleavage of the epidermis with corps ronds and grains(Fig.1B).Base on the clinical manifestation and histological findings. The initial diagnosis diagnosis was considered as concurrence of Darier’s Disease and Depression. For the final diagnosis, the detection of mutations in ATP2A2 was performed.

Figure 1. The clinical and histopathological features of the patient with Darier’s disease.(A)Photograph showing the clinical features of Darier’s disease comprising brown,harsh keratotic papules and plaques on the back.(B)Histopathologic examination of skin biopsy specimens showing the unique characteristics of focal acantholysis in the suprabasal layer of the epidermis with corps ronds and grains.(Hematoxylin-eosin stain;×200).

Figure 2. Chromatograms of the mutated and matched normal sequences. (A) The mutated sequences: c.2993_2994del (p.Val998Alafs∗33) at ATP2A2 in the patient with sporadic Darier’s disease. (B) The matched normal sequences from a healthy control subject.

In accordance with the principles of the Declaration of Helsinki,a peripheral blood sample was analyzed after the attainment of informed consent from the patient and approval from the Ethics Committee of Fudan University.Genomic DNA was isolated from the peripheral blood sample. Primer 3.0 software (http://simgene.com/Primer3)was used to design specific primers to amplify the coding region of ATP2A2.The coding regions and more than 50bp of the exon-intronic boundary sequence were amplified by PCR and the PCR products were purified and sequenced.

Sequence analysis showed that the nucleotides“TG”at cDNA position 2993_2994 in exon 20 of ATP2A2 were deleted on one allele(Fig.2).This small deletion mutation in ATP2A2 could cause a frame-shift of the amino acid sequence, with premature translation of the protein at position 1030(p.Val998Alafs∗33).The mutation site was located in the last transmembrane domain of the sarco/endoplasmic reticulum ATPase type 2 (SERCA2) Ca2+pump protein. This mutation c.2993_2994del (p.Val998Alafs∗33) was not detected in 192 unrelated healthy control subjects.

After final diagnosis of DD was made,topic compound lactic acid cream (Each 10g contains 1.2g of lactic acid and 1.5g of urea) twice per day was then administered.After one month, the symptoms were relieved, but it was easy to relapse after stopping the cream.During the followup by the writing, the patient is using the cream for longterm maintenance treatment.

Discussion

DD is caused by SERCA2 mutations. SERCA2 has two isoforms: SERCA2a and 2b. SERCA2a is expressed in cardiomyocytes and slow-twitch skeletal muscles,whereas SERCA2b is expressed in almost all tissues, including the epidermis. SERCA2 is involved in the transport of Ca2+from the cytosol to the lumen of the endoplasmic reticulum,where Ca2+is stored at a higher concentration.However, the mechanisms underlying the dissociation of epidermal keratinocytes and dyskeratosis in response to perturbations in calcium homeostasis remain unknown.

In addition to characteristic skin manifestations, DD is associated with several extracutaneous manifestations. In particular, DD is associated with neuropsychiatric disorders, including depression, bipolar disorder, epilepsy,and learning difficulties.1–3A large study performed in Sweden found that individuals with DD have 4.3 and 2.3 times higher risks of bipolar disorder and schizophrenia,respectively, than the general population.4The same authors conducted another matched cohort study that suggested that individuals with DD have a six-fold increased risk of being diagnosed with intellectual disability.5Previous genome-wide association studies identified ATP2A2 as a schizophrenia-associated loci,which implies that calcium signaling and calcium channel activity play a role in the pathogenesis of a number of major psychiatric disorders.6-7However, no clear genotype-phenotype correlation has been found between DD and neuropsychiatric manifestations.Therefore,the role of ATP2A2 variants in the development of psychiatric disease in DD remains unclear.

A previous review divided the mutations reported to cause DD into two categories: (a) likely gene disrupting(LGD)mutations(frameshift,splice site,nonsense,gain of stop codon,or loss of start codon)and(b)protein altering mutations (missense or inframe-insertion/deletions).8The authors found significantly higher rates of LGD mutations in patients with DD with concurrent neuropsychiatric disorders than in patients with DD without neuropsychiatric disorders,and concluded that psychiatric illnesses in DD may be caused by a pleiotropic effect of loss-offunction mutations of ATP2A2.9Similarly, another large study of 75 unrelated individuals with DD also found that LGD mutations were more prevalent in individuals with DD with neuropsychiatric phenotypes than in those without such phenotypes.9

In our patient with severe DD,the persistent depression was probably a psychological reaction to his poor skin condition. However, previous studies have showed a relatively high prevalence of psychiatric problems in patients with DD with mild skin symptoms, suggesting that neuropsychiatric symptoms may not be due to the presence of severe and chronic skin symptoms. The small deletion mutation in ATP2A2 in the present patient may have caused a frame-shift of the amino acid sequence,with premature translation of the protein at position 1030 (p.Val998Alafs∗33).This mutation site was located in the last transmembrane domain of the SERCA2 Ca2+pump protein, which has previously been classified as an LGD mutation.8To the best of our knowledge, there are no reports of mainland Chinese patients with concurrent DD and depression. This suggests that psychiatric disorders may be being overlooked in Chinese patients with DD,and that there is a need for Chinese dermatologists to be aware of the possibility of such neuropsychiatric comorbidities.

In conclusion, we reported a case of a patient with concurrent DD and depression, and identified an LGD mutation,which is consistent with previous research.This finding could enrich and update the Human Gene Mutation Database of ATP2A2 mutations in DD. The underlying mechanism of the correlation between the mutation in ATP2A2 and neuropsychiatric phenotypes in DD remains unclarified and warrants further investigation.