Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo‐optico‐neuropathy (SMON) (2024)

Associated Data

Data Availability Statement

Abstract

Keywords: ABCC11, ABCC4, clioquinol, Japanese, subacute myelo‐optico‐neuropathy

1. INTRODUCTION

Subacute myelo‐optico‐neuropathy (SMON), a neurological disorder associated with clioquinol administration, is a serious drug‐induced disorder. Reports have indicated that 1%–4% of patients who were administered clioquinol developed SMON. SMON has occurred in ~10,000 people, and ~5% of SMON patients have died from the disease (Meade, 1975). In recent years, because of the aging of patients, the number of surviving SMON patients has decreased each year. In our report in 2019, ~1100 SMON patients with various neurological sequelae were still alive in Japan. The pathomechanism of this neurological disease is considered to be dependent on the dose of clioquinol (Sobue et al., 1973). SMON and similar disorders have also been reported in European and Indian populations (Gilland, 1984; Ricoy et al., 1982; Wadia, 1984), but the most severe form of this neurological disease occurs with a high frequency in Japan (Kono, 1971; Meade, 1975; Nakae et al., 1973). Therefore, it is possible that the unique genetic background of Japanese people induces susceptibility to this neurological disease caused by clioquinol administration. Clioquinol was considered a useful medication with strong antibacterial activity during the 1950s and 1960s in Japan. Recently, clioquinol has been suggested for the treatment of neurodegenerative diseases such as Alzheimer's disease (Billings et al., 2016; Cherny et al., 2001) and tumors (McInerney et al., 2018; Perez et al., 2016). Thus, it is essential to analyze the effects of genetic background on clioquinol metabolism before considering the introduction of clioquinol and its analogues in Japan to prevent the recurrence of SMON.

In 2019, Perez et al. (2019) suggested an association among clioquinol administration, the development of SMON in Japanese people, and ABCC4 (OMIM: 605250) and ABCC11 (OMIM: 607040) polymorphisms. ABCC4 and ABCC11 are genes related to the cAMP transport pump. ABCC4, which is encoded by the ABCC4 gene, is associated with the transport of lipophilic organic anions across the plasma membrane and may also be involved in prostaglandin‐mediated cAMP signaling in ciliogenesis (Hardy et al., 2019). The ABCC4 rs3765534 polymorphism has been reported to dramatically reduce transporter function by disrupting localization of the ABCC4 protein in the plasma membrane (Krishnamurthy et al., 2008). ABCC11, encoded by the ABCC11 gene, is associated with transporting lipophilic organic anions across the plasma membrane, similar to ABCC4 (Toyoda et al., 2016). The ABCC11 rs17822931 polymorphism is involved in apocrine gland secretion and has been associated with a certain type of earwax and the onset of axillary osmidrosis (Super Science High School Consortium, 2009; Toyoda et al., 2009). The ABCC4 rs3765534 (c.2269G>A, p.Glu757Lys) and ABCC11 rs17822931 (c.538G>A, p.Gly180Arg) polymorphisms are both more common in Japanese people than in Europeans. To confirm the above‐mentioned hypothesis reported by Perez et al. (polymorphisms in ABCC4 and ABCC11 are associated with clioquinol administration and development of SMON in Japanese people), we performed a genetic analysis using a large database of Japanese SMON patients.

2. MATERIALS AND METHODS

3. RESULTS

A summary of the clinical information of SMON patients enrolled in this study is shown in Table ​Table1.1. Many SMON patients are still living with sequelae of variable severity. The frequencies of ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms among the races registered in the gnomAD are shown in Table ​Table2.2. Compared with other races, the allele frequency of ABCC4 rs3765334 Alt (A) was much higher in the Japanese population. The allele frequencies of ABCC11 rs17822931 Ref (G) and Alt (A) were reversed in the East Asian population, including Japanese people, compared with other populations. The frequency distributions of ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms in SMON patients and healthy Japanese people listed in the databases (HGVD and iJGVD) are shown in Table ​Table3.3. Statistical analysis showed no significant difference in the frequency of these two polymorphisms between SMON patients and healthy Japanese people.

4. DISCUSSION

In this study, we evaluated the genetic variants of ABCC4 and ABCC11 that were recently suggested as possible genetic susceptibility factors for SMON. However, the ABCC4 rs3765534 and ABCC11 rs17822931 polymorphisms showed no significant difference in frequency between SMON patients and healthy Japanese people. Furthermore, we found many SMON patients who lacked these two polymorphisms. The association between the development of SMON and these two polymorphisms could not be verified, at least in terms of allele frequency.

Tateishi et al. reported an association between the development of SMON and clioquinol administration in experiments with an animal disease model (Tateishi et al., 1971), and this association was verified because the occurrence of new SMON cases completely disappeared after clioquinol use was banned (Nakae et al., 1973). However, the specific mechanism by which clioquinol causes nerve damage and induces SMON has not been elucidated. At present, several hypotheses regarding the pathomechanism of SMON have been proposed. Kawamura et al. (2014) reported that the neurological damage associated with the disease is caused by reactive oxygen species, Schaumburg et al. and Kimura et al. showed that copper deficiency was caused by copper chelation by clioquinol (Kimura et al., 2011; Schaumburg & Herskovitz, 2008), and Katsuyama et al. (2012) showed that double‐strand DNA breaks induced by clioquinol cause ATM activation and concomitant activation of p53. Katsuyama et al. (2021) also showed that zinc influx was caused by the ionophore effect of clioquinol, and copper accumulation was caused by oxidation of ATOX1. However, none of these factors have been shown to be linked to susceptibility to SMON. Although clioquinol‐induced neurological disorders have been reported in European (Gilland, 1984; Ricoy et al., 1982) and Indian populations (Wadia, 1984), the majority of SMON patients are Japanese people. Therefore, it has long been suggested that a race‐specific genetic background might be associated with the development of SMON (Kono, 1971; Nakae et al., 1973). However, at present, no gene mutations or polymorphisms have been reported to be clearly associated with the development of SMON.

In recent years, many reports have described the beneficial effects of clioquinol and similar substances for neurodegenerative and oncological diseases. Therefore, it is important to elucidate the mechanism responsible for susceptibility to SMON. Several reports have found that the metal chelating effect of clioquinol may be useful in preventing the development of Alzheimer's disease (Billings et al., 2016; Cherny et al., 2001). Several reports have also found that the inhibitory effect of clioquinol on ATP binding cassette subfamily C (ABCC) transporter function may be useful for inhibiting the growth of hematological tumors (McInerney et al., 2018; Perez et al., 2016). Because ABCC4, 5, and 11 are transporters that can be affected by clioquinol, Perez et al. analyzed the regional distribution of polymorphisms of the associated genes in the Japanese population (Super Science High School Consortium, 2009) in combination with reports on the residential areas of SMON patients (Kono, 1971) and reported that the ABCC4 rs3765534 and ABCC11 rs17822931 polymorphisms were candidate gene variants associated with the development of SMON (Perez et al., 2019). However, the association between these polymorphisms and the development of SMON was not demonstrated in in vitro functional experiments, and the frequencies of these polymorphisms in SMON patients are still unknown. Our study reports the frequencies of these polymorphisms in surviving SMON patients, but the association between the development of SMON and these two polymorphisms could not be verified.

One hypothesis is that the development of SMON is associated with a unique Japanese genetic background. To prevent a similar drug‐induced disorder in the future, it is important to understand the pathogenesis of SMON. Therefore, we will continue to search for other genetic factors associated with SMON development using the largest database of SMON patients. It is assumed that oxidative stress in neurons may play a key role in the development of SMON (Kawamura et al., 2014). We are currently focusing on the cytoplasmic two‐electron reductase encoded by the NQO1 gene (OMIM: 125860, NM_000903.3), which is an enzyme associated with oxidative stress, as one possible factor. In addition, comprehensive analysis, including genome‐wide association studies, is required in future research. Two limitations in this study should be noted. We have obtained the largest dataset of SMON patients worldwide, but it is unlikely that there will be any new SMON patients in the future. Therefore, it would be impossible to collect more patients than those included in our study. The second limitation of this study is the lack of data, including the total dose and duration of clioquinol administration in SMON patients. In addition, we were not able to determine the patients’ residential areas at SMON onset to perform detailed research on environmental factors.

5. CONCLUSION

No clear association was found between the ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms and the development of SMON. It will be necessary to investigate other genetic background factors involved in the development of SMON in the future.

CONFLICT OF INTEREST

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ETHICAL CONSIDERATIONS

This study was carried out under approval by the ethics review committee on medical research of Gifu University (Protocol number: 29‐209), and the research collaborator's institution also provided ethical approval.

ACKNOWLEDGMENTS

This study was conducted with the cooperation of the following members of the SMON research group: Seiichiro Sugimoto (Department of Neurology, National Hospital Organization, Miyazaki Higashi Hospital, Miyazaki, Japan), Haruki Koike (Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan), Hidenori Matsuo (National Hospital Organization, Nagasaki Kawatana Medical Center, Nagasaki, Japan), Masaaki Konagaya (National Hospital Organization Suzuka Hospital, Mie, Japan), Mika Jikumaru (Department of Neurology, Faculty of Medicine, Oita University, Oita, Japan), Takao Mitsui (Department of Neurology, Tokushima National Hospital, Tokushima, Japan), Mie Takahashi (Department of Neurology, Kochi Memorial Hospital, Kochi, Japan), Kenichi Sakai (Department of Neurology, National Hospital Organization Minami‐Okayama Medical Center, Okayama, Japan), Yasuhiro Hamada (Department of Gastroenterology & Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan), Keiji Chida (Department of Neurology, National Hospital Organization Iwate Hospital, Iwate, Japan), Norio Ohkoshi (Course of Neurology, Department of Health Sciences, Tsukuba University of Technology, Ibaraki, Japan), and Manabu Inoue (Department of Neurology, Osaka City General Hospital, Osaka, Japan). We thank these people for their contributions to this research and for recruiting SMON patients for this study.

Notes

Matsumoto, H., Sasai, H., Kawamoto, N., Katsuyama, M., Minamiyama, M., Kuru, S., f*ckao, T., & Ohnishi, H.; SMON research group members(2022). Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo‐optico‐neuropathy (SMON). Molecular Genetics & Genomic Medicine, 10, e1845. 10.1002/mgg3.1845 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Funding information

This study was supported by a Health and Labor Sciences Research Grant for Research on Intractable Diseases from The Ministry of Health, Labour and Welfare of Japan (H28‐Intractable, etc. (Intractable)‐Designated‐110; H29‐Intractable, etc. (Intractable)‐Designated‐001; H30‐Intractable, etc. (Intractable)‐Designated‐003; Grant No. 2019‐Intractable, etc. (Intractable)‐Designated‐001; Grant No. 2020‐Intractable, etc. (Intractable)‐Designated‐006).

DATA AVAILABILITY STATEMENT

Research data are not shared.

REFERENCES