The discovery of acatalasemia (lack of catalase in the blood) and its significance in human genetics

Abstract

Catalase, a heme-containing antioxidant enzyme, was once considered essential for human survival. It is widely distributed in the human body and is particularly abundant in red blood cells. The term “acatalasemia” first appeared in the Proceedings of the Japan Academy in 1951, drawing global attention to families genetically deficient in catalase. This deficiency not only altered the significance of catalase but also played a pioneering role in human genetics during an era of limited genetic methodology. In this article, we examine the discovery of acatalasemia by an otolaryngologist during surgery on an 11-year-old girl. This remarkable journey led to epoch-making research spanning biochemistry, hematology, and human genetics.

1. Introduction

Catalase, a heme protein, is known for its role in breaking down hydrogen peroxide into water and oxygen.^1),2) This enzyme is prevalent in various life forms, including microorganisms, plants, and animals, with notable concentrations in the liver, kidney, and red blood cells in animals. The discovery of acatalasemia, a condition characterized by a deficiency of catalase in the blood, can be traced back to 1946, the year after World War II ended.³⁾ This discovery was made by Dr. Shigeo Takahara, then a young professor of otorhinolaryngology at Okayama Medical University, who was the primary surgeon for a patient presenting with severe oral gangrene. Subsequent research revealed that catalase deficiency led to an accumulation of hydrogen peroxide, disrupting oxygen supply and causing necrotic inflammation in the oral cavity.^4)-8)

The significance of this discovery extended beyond the identification of a rare oral gangrenous disease. Research on acatalasemia, initiated with a series of papers published in the Proceedings of the Japan Academy from 1951 to 1952, gained international recognition upon its publication in the Lancet.⁸⁾ This work made a substantial contribution to the field of human genetics.

2. Discovery of a rare gangrenous oral disease

The initial case involved an 11-year-old girl presenting with a fever of 38–39 and osteonecrosis of the maxilla. The necrotic tissue filled the perforated center of the maxilla, which had opened into the maxillary sinus, and emitted a foul odor. During a partial maxillectomy, Dr. Takahara applied a hydrogen peroxide solution (OXYFULL^TM) to the affected area. To his surprise, no oxygen gas bubbles were generated, and the blood immediately turned dark brown. Initially, Dr. Takahara suspected that the nurse had mistakenly given him silver nitrate instead of hydrogen peroxide. However, after injecting a normal saline solution to neutralize it and observing the blood return to its normal color, he tried a different bottle of OXYFULL^TM and observed the same results. This unusual blood finding prompted further research. The patient’s brother, who was later discovered to have a catalase deficiency, had undergone a partial maxillectomy by a different surgeon several years earlier. He had exhibited the same blood finding when a hydrogen peroxide solution was applied, but this observation was not investigated further at the time. In 1947, Takahara et al. reported the first case series of oral gangrene, likely due to catalase deficiency, which was observed in three siblings.³⁾ They noted that the siblings’ parents were consanguineously married. In terms of dental disease, the patients’ father, two aunts, and a grandfather all suffered from severe alveolar pyorrhea. The father had lost all his teeth before the age of 30.

In the subsequent year, they published their inaugural paper on the disease, detailing two families exhibiting similar oral and blood findings.⁴⁾ The existence of another family lineage with the same symptoms suggested the presence of a disease attributable to genetic catalase deficiency. In their paper, they quantified the patients’ catalase deficiency using Inoue’s permanganate method⁹⁾ and observed a unique blackening reaction of the blood in vitro (Fig. 1). When a patient’s blood was exposed to a small amount of hydrogen peroxide, it remained black (a mixture of methemoglobin and hematin, measured at 625 nm using a spectrophotometer) for an extended period. However, upon the addition of a large amount of hydrogen peroxide, the black color began to fade after about 30 min, transitioning to a light-reddish brown, then lemon-yellow, and eventually becoming transparent. This transparent substance was identified as propentdyopent, named by Fischer and Müller¹⁰⁾ as the end product of hemoglobin. They also demonstrated that Bingold’s pentdyopent reaction,¹¹⁾ which further reduces propentdyopent, resulted in the production of rose-red pentdyopent (525 nm).

Fig. 1

Ulcerative lesions of the oral cavity and the reaction of blood samples upon the addition of hydrogen peroxide. A) Early ulceration of the lower gingiva. B) A deep ulcer that perforates the maxillary sinus. C) Blackening of acatalasemic (left) and oxygen bubbles in normal blood samples (right). Note that these photographs are of later cases, not of the first 11-year-old girl.

To understand the mechanism of oral gangrene, they conducted an experiment where hemolytic streptococci or pneumococci, collected from the patient’s oral cavity, were inoculated on blood agar plates prepared from the patient’s blood. There was no difference in colony growth on these plates compared with control plates made from healthy human blood. However, after 24 h, a broad, transparent ring appeared in place of the usual hemolytic rings, regardless of whether the conditions were aerobic or anaerobic. It is well known that hydrogen peroxide is produced when hemolytic streptococci or pneumococci grow. The hydrogen peroxide generated from the colonies on the patient’s blood agar plate likely oxidized the oxyhemoglobin to methemoglobin. As the oxidation continued, the media around the colony gradually faded, eventually resulting in transparent propentdyopent.^4),5) Based on these experiments, they proposed the following pathophysiology: Small wounds on the gingiva provide a suitable medium for oral bacteria. In normal individuals, catalase readily neutralizes the hydrogen peroxide produced by these bacteria. However, in individuals lacking catalase in their blood, the hydrogen peroxide oxidizes the blood around the lesion, depriving it of oxygen and causing necrosis. Consequently, the bacteria proliferate further, producing more hydrogen peroxide and oxidizing oxyhemoglobin. This process can transform a small wound into a deep ulcer characterized by prominent necrosis but minimal inflammation.^4),5)

3. Trilogy published in the Proceedings of the Japan Academy

The term “acatalasemia” made its debut in English literature in a 1951 bulletin from the Proceedings of the Japan Academy.⁵⁾ This pivotal article summarized observational and experimental studies conducted up to that point and reported a total of nine cases from three families, all of which involved consanguineous parents (Fig. 2).^5),8) Takahara et al. described the excitement over the discovery of a deficiency in catalase, an enzyme previously considered essential for human survival. They also showed interest in substances that could compensate for this deficiency. However, it was not until 1957 that another antioxidant enzyme, glutathione peroxidase, was discovered.¹²⁾

In their second paper, the group quantified catalase in the blood and tissues of both patients and healthy controls, as well as selected animals.⁶⁾ To ensure the reliability of the quantification, they employed Warburg’s manometric method in addition to Inoue’s permanganate method. The study found that the catalase activity in patients with acatalasemia was approximately 1/1,000 that of healthy controls. In ducks and geese, the catalase activity was 1/50 and 1/200, respectively. Notably, when hydrogen peroxide was added to their blood, it immediately turned black, and no bubbles were observed. Despite these findings, catalase was detected in the liver, kidneys, and small intestine at levels comparable to those in other animals, such as rabbits. This raised questions about the catalase activity in these organs in acatalasemic patients, but due to a lack of autopsy cases, these questions remained unanswered.

Fig. 2

Family trees of nine patients diagnosed with acatalasemia (adopted from Lancet 2, 1101–1104).⁸⁾ All nine cases from three families involved consanguineous parents.

The third report added two families from eastern Japan, discovered by Yoshiya,¹³⁾ to the three families from western Japan previously reported.⁷⁾ These observations led to the conclusion that acatalasemia is a single-gene recessive trait. The trilogy of articles published in the Proceedings of the Japan Academy formed the core of the first phase of acatalasemia research. Notably, the term “acatalasemia” was deemed more appropriate than “acatalasia,” because not all organs had been proven to be deficient in catalase.

4. Publication in the Lancet

The discovery of families genetically deficient in catalase, an enzyme previously thought to be essential for human survival, was published in the Lancet in 1952, attracting global attention. The journey to this publication was intriguing. Dr. Takahara, recognizing the significance of not only discovering a new familial disease but also the survival of humans deficient in catalase, initially sought the recommendation of an international scholar. He approached Professor Samuel Crowe, a renowned otolaryngologist at Johns Hopkins University. Professor Crowe first considered publishing this work in the Annals of Otology, Rhinology, and Laryngology. However, after consulting with Professor Victor Najjar, a leading authority on enzymology in the U.S., they concluded that the absence of catalase in the blood was implausible, and even if true, it was unlikely that the lesions would be confined to the oral cavity.

Despite this setback, Dr. Takahara responded with detailed experimental results and color videos of blood findings, which eventually convinced the U.S. professors. Meanwhile, Professor Tomihide Shimizu of Okayama University, known for his significant contribution to the study of bile acids, had sent the paper to Professor Geoffrey Haslewood in London. Professor Haslewood, a biochemistry professor at Guy’s Medical College, sought the opinion of a physiology professor at Oxford University and recommended Dr. Takahara’s work for publication in the Lancet. Upon publication, he expressed his appreciation for the thorough investigation of a new disease and was pleased to have the paper in the journal.

Reflecting on this process, Dr. Takahara acknowledged the severity of the criticism from leading western scholars toward research papers, viewing it as an ideal attitude in the pursuit of truth. He also expressed deep appreciation for Professor Haslewood’s kindness and noble character.

5. Identification of heterozygotes and contribution to human genetics

In the late 1950s, Takahara and colleagues shifted their focus to the “carrier state” observed in acatalasemic families. In these families, individuals did not develop oral disease, but their catalase activity was approximately half of that observed in normal controls (Fig. 3).¹⁴⁾ Through experimental studies, they demonstrated that this reduction in catalase activity was due to the presence of half the normal amount of catalase protein rather than the presence of inhibitors.^15)-19) This groundbreaking research marked a significant advancement in human genetics, especially at a time when identifying carriers in autosomal recessive disorders was challenging. It enabled the practical measurement of gene frequencies in specific populations, a task that was previously only achievable through indirect estimation formulas.

Fig. 3

Distribution of catalase activity among members of the five families with acatalasemia (adopted from Science 130, 333–334).¹⁴⁾ Catalase activities between normal subjects and heterozygotes were clearly differentiated.

In 1908, Sir Archibald Garrod introduced the concept of “inborn errors of metabolism,” citing four hereditary metabolic defects (alkaptonuria, albinism, pentosuria, and cystinuria) as examples.²⁰⁾ Since then, approximately a dozen clinical tests had been developed to detect carriers in autosomal recessive disorders. However, there was significant overlap in activity between normal subjects and heterozygotes. In contrast, acatalasemia presented a unique feature: the activities of those with the condition were clearly differentiated. Leveraging this, Dr. Takahara and his colleagues conducted a population-based study of heterozygotes, termed hypocatalasemia, and created a gene frequency map of Japan. This map also revealed the distribution of the gene among Koreans residing in Japan. For this pioneering work, which significantly contributed to human genetics during a time when genetic analysis technology was limited, Dr. Takahara was awarded the newly established prize of the Japan Society of Human Genetics in 1960, followed by the Asahi Prize in 1961 and the Japan Academy Prize in 1964.

The gene frequency map showed a high occurrence along the Korean coastline of Tsushima, with values between those of Korean residents in Japan and inland Japanese (Fig. 4).²¹⁾ This suggested that many of the heterozygotes might have originated from the Korean side. Consequently, from 1965, Takahara et al. conducted a survey of 14,681 residents of Ryukyu (Okinawa) and 21,789 of Taiwan in cooperation with the Ryukyu and Republic of China governments. The distribution in north, central, and south China was estimated based on the birthplace of Taiwanese residents, leading to the completion of a genetic map of East Asia (Fig. 5).^22),23) This map suggested that, with regard to the acatalasemic gene, Japanese are closely related to the Chinese and Koreans and less so to the people of Okinawa. Thus, the discovery of acatalasemia in a single girl even shed light on the roots of the Japanese people.

Indeed, the second phase of acatalasemia research made significant contributions to human genetics. The field survey, which continued until 1985, reported a total of 108 cases across 53 families.²⁴⁾ The distribution of cases expanded beyond Asia, reaching as far as Switzerland, Israel, Germany, and Peru. Dr. Takahara’s authentic genetic approaches were truly pioneering in the field of molecular anthropology, especially considering the limitations of genetic methodology at the time.

Fig. 4

Distribution of ‘hypocatalasemia’ (heterozygotes) in Japan (modified from Igaku No Ayumi 54, 334–336).²¹⁾

Fig. 5

Distribution of ‘hypocatalasemia’ (heterozygotes) in East Asia (modified from Okayama Igakukai Zasshi 80, 1275–1280).²³⁾

6. Acatalasemia from a modern perspective

6.1. Phenylketonuria

[1]Phenylketonuria[1](PKU) stands as the earliest documented instance of a single enzyme deficiency leading to a severe systemic disease. The condition was uncovered by Følling, a pediatric resident in Norway, during his examination of two mentally challenged siblings in 1934. With a background in chemistry preceding his medical studies, Følling astutely noted an unusual green coloration instead of the expected purple in a urine ketone test using ferric chloride.²⁵⁾ Subsequent advancements in understanding PKU unfolded over the years: Jervis identified phenylalanine hydroxylase deficiency in patients, the enzyme responsible for metabolizing phenylalanine to tyrosine, in 1950²⁶⁾; Bickel demonstrated the preventive effect of a low-phenylalanine diet on intellectual impairment in 1953²⁷⁾; and Guthrie developed a simple and reliable blood spot test for PKU screening in 1963.²⁸⁾ The discovery of PKU holds profound significance in medical history, illuminating critical lessons such as the pivotal role of early detection and dietary management in disease control, as well as the essentiality of screening tests in therapy.

During the 1940s and 1950s, concurrent with the study on PKU, acatalasemia emerged as a specific disease. Despite a significant enzyme deficiency in red blood cells, it caused localized oral lesions. The condition likely manifested in early 20th-century Japan, a period marked by poor nutritional status and inadequate medical care. Notably, the concept of compensatory pathways for essential survival enzymes had not yet been established, and the existence of families deficient in catalase was not readily accepted. The discovery of acatalasemia brought awareness of this issue, and in 1957, glutathione peroxidase, an antioxidant compensating for catalase, was discovered.¹²⁾ Fortunately, the frequency of acatalasemia in Japan is low (1/240,000) compared with PKU (1/80,000), and the incidence of symptomatic acatalasemia has decreased with improvements in nutrition and medical care. However, there are still case reports of unexpected methemoglobinemia encounters when hydrogen peroxide is used during oral surgery.²⁹⁾

6.2. Elucidation of causal genetic abnormalities

The genetic abnormality responsible for acatalasemia was identified with the advancement of molecular biology. In 1986, the amino acid sequence of the human catalase gene (CAT) was determined and found to consist of 13 exons.^30),31) In 1990, Wen et al. identified a splice region mutation (NM_001752.4:c.480+5G >A) in a Japanese patient.³²⁾ Dr. Takahara had previously noted that patients with acatalasemia have only 1/1000th of the catalase protein of normal subjects,⁶⁾ and it is now understood as the rare normal product translated despite the mutation in the splice region. Subsequently, two less frequent frameshift mutations (NM_001752.4: c.358del and c.203_204dup) were reported.^33),34) In the era of genomic science, several additional abnormalities have been registered in public databases. According to the variant database of 54,000 Japanese individuals compiled by the Tohoku Medical Megabank Organization (ToMMo, https://jmorp.megabank.tohoku.ac.jp), the allele frequency of c.480+5G >A is 0.001308, aligning with the gene frequency of 0.00173 derived from the field survey by Takahara and colleagues.³⁵⁾ Their survey extending research to East Asia should also be commended. The allele frequency of acatalasemia is now known to be 0.000385 in East Asia and 0.00002 globally, according to the gnomAD database.³⁶⁾

6.3. Common disease and acatalasemia

An increase in hydrogen peroxide due to catalase deficiency may contribute to the development of several diseases, including diabetes. Góth et al., who identified a gene mutation in Hungarian type acatalasemia,³⁴⁾ also reported a correlation between Hungarian patients with type 2 diabetes and acatalasemia.³⁷⁾ Furthermore, Yamada et al. conducted an exome-wide association study in the Japanese population and reported that a polymorphism in the CAT gene (rs139421991) is a risk factor for diabetes.³⁸⁾ Diabetes mellitus is a disorder influenced by multiple genetic and environmental factors. If a genetic test for risk predisposition were available, the CAT gene may potentially be included in the analysis.

7. Conclusion

The recessive acatalasemic gene, which has an allele frequency of more than 0.1% in the Japanese population, was first identified by a meticulous otolaryngologist. The disease manifested as a necrotic oral condition during a time characterized by frequent consanguineous marriages, poor nutritional conditions, and inadequate medical care. This discovery not only redefined the significance of the antioxidant enzyme catalase but also made a pioneering contribution to human genetics. It served as a biochemical marker at a time when genetic methodology was still in its infancy. We extend our appreciation for the careful observation, foresight, and persistent research efforts that led to this significant discovery.

Acknowledgements

The authors would like to thank Ms. Yuko Tsunoda and Ms. Nodoka Harada for their assistance in collecting and organizing historical literature.

Notes

Edited by Hiroyuki MANO, M.J.A.

Correspondence should be addressed to: M. Ando, Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan (e-mail: [e-mail]).

Footnotes

This paper commemorates the 100th anniversary of this journal and introduces the following paper previously published in this journal. Takahara, S. (1951) Acatalasemia (lack of catalase in blood) and an oral progressive gangrene. Proc. Jpn. Acad. 27 (6), 295-301 ( https://doi.org/10.2183/pjab1945.27.295).

References

• 1)  Loew, O. (1900) A new enzyme of general occurrence in organisms. Science 11, 701-702.
• 2)  Sumner, J.B. and Dounce, A.L. (1937) Crystalline catalase. Science 85, 366-367.
• 3)  Takahara, S. and Miyamoto, H. (1948) Three cases of progressive oral gangrene due to lack of catalase in the blood (Proceedings of the 56th Tyugoku Branch Meeting, Japanese Society of Otolaryngology, Jul. 1947, Okayama). Nihon Jibiinkoka Gakkai Kaiho 51, 163 (in Japanese).
• 4)  Miyamoto, H. and Takahara, S. (1949) Clinical and experimental studies on progressive oral gangrene probably due to lack of catalase in the blood. Jibiinkoka 21, 53-56 (in Japanese).
• 5)  Takahara, S. (1951) Acatalasemia (lack of catalase in blood) and an oral progressive gangrene. Proc. Jpn. Acad. 27, 295-301.
• 6)  Takahara, S., Mihara, S., Tsugawa, K. and Doi, M. (1952) Acatalasemia II. Contents of catalase in blood and tissues of men and animals. Proc. Jpn. Acad. 28, 383-387.
• 7)  Takahara, S., Sato, H., Doi, M. and Mihara, S. (1952) Acatalasemia III. On the heredity of acatalasemia. Proc. Jpn. Acad. 28, 585-588.
• 8)  Takahara, S. (1952) Progressive oral gangrene probably due to lack of catalase in the blood (acatalasaemia); report of nine cases. Lancet 2, 1101-1104.
• 9)  Inoue, B., Ochi, M. and Shirai, H. (1920) Quantification method for catalase. Tokyo Igakkai Zasshi 34, 1190-1196 (in Japanese).
• 10)  Fischer, H. and Müller, A. (1937) Über die Pentdyopent-Reaktion. I. Mitteilung. Hoppe Seylers Z. Physiol. Chem. 246, 43-58.
• 11)  Bingold, K. (1935) Weitere Untersuchungen zur Formulierung eines biologisch-chemischen Blutkreislaufes. Klin. Wochenschr. 36, 1287-1289.
• 12)  Mills, G.C. (1957) Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown. J. Biol. Chem. 229, 189-197.
• 13)  Yoshiya, M. (1952) ``Anenzymia catalasea,'' a new type of constitutional abnormality. Kokubyo Gakkai Zasshi 19, 18-25 (in Japanese).
• 14)  Nishimura, E.T., Hamilton, H.B., Kobara, T.Y., Takahara, S., Ogura, Y. and Doi, K. (1959) Carrier state in human acatalasemia. Science 130, 333-334.
• 15)  Takahara, S., Hamilton, H.B., Neel, J.V., Kobara, T.Y., Ogura, Y. and Nishimura, E.T. (1960) Hypocatalasemia: a new genetic carrier state. J. Clin. Invest. 39, 610-619.
• 16)  Ogata, M. and Takahara, S. (1962) Paper electrophoretic studies on the catalase protein in acatalasemic blood extract (stage 3 by Herbert-Pinsent). Proc. Jpn. Acad. 38, 361-364.
• 17)  Takahara, S., Ogata, M., Kobara, T.Y., Nishimura, E.T. and Brown, W.J. (1962) The ``catalase protein'' of acatalasemic red blood cells. An electrophoretic and immunologic study. Lab. Invest. 11, 782-790.
• 18)  Takahara, S. and Ogata, M. (1962) Spectrometric studies on the catalase in acatalasemic red blood cell extracts, stages 2 and 3 by Herbert-Pinsent. Proc. Jpn. Acad. 38, 779-782.
• 19)  Ogata, M. and Takahara, S. (1962) Quantitative precipitin studies on catalase protein in hemolysate and acetone extract from acatalasemia and hypocatalasemia. Proc. Jpn. Acad. 38, 783-788.
• 20)  (a) Garrod, A.E. (1908) Inborn errors of metabolism. Lecture I. Lancet 172, 1-7. (b) Garrod, A.E. (1908) Inborn errors of metabolism. Lecture II. Lancet 172, 73-79. (c) Garrod, A.E. (1908) Inborn errors of metabolism. Lecture III. Lancet 172, 142-148. (d) Garrod, A.E. (1908) Inborn errors of metabolism. Lecture IV. Lancet 172, 214-220.
• 21)  Ogura, Y. (1965) The distribution of acatalasemia and hypocatalasemia (Proceedings of the 9th annual meeting of the Japan Society of Human Genetics., Nov. 1964, Wakayama). Igaku No Ayumi 54, 334-336 (in Japanese).
• 22)  Takahara, S. (1968) Acatalasemia in Japan. In Hereditary Disorders of Erythrocyte Metabolism (ed. Beutler, E.). Grune & Stratton, Inc., New York, pp. 21-40.
• 23)  Takahara, S., Ogura, Y., Orita, Y., Masuda, Y., Saito, R., Seto, T. et al. (1968) Field survey of acatalasemic gene among the population in Formosa. Okayama Igakukai Zasshi 80, 1275-1280 (in Japanese).
• 24)  Takahara, S., Ogura, Y., Masuda, Y., Nishioka, K., Nishizaki, K., Sugiura, T. et al. (1986) Field survey of acatalasema and hypocatalasemia from 1949 through 1985. Okayama Igakukai Zasshi 98, 577-586 (in Japanese).
• 25)  Fø lling, A. (1934) Excretion of phenylpyruvic acid in urine as a metabolicnomaly in connection with imbecility. Nord. Med. Tidskr. 8, 1054-1059.
• 26)  Jervis, G.A. (1950) Excretion of phenylalanine and derivatives in phenylpyruvic oligophrenia. Proc. Soc. Exp. Biol. Med. 75, 83-86.
• 27)  Bickel, H., Gerrard, J. and Hickmans, E.M. (1953) Influence of phenylalanine intake on phenylketonuria. Lancet 265, 812-813.
• 28)  Guthrie, R. and Susi, A. (1963) A simple phenylalanine method for the detection of phenylketonuria in large populations of newborn infants. Pediatrics 32, 338-343.
• 29)  Hamada, Y., Kameyama, Y., Iizuka, T., Ishizaki, T., Nishiyama, T. and Isshiki, A. (2004) Methemoglobinemia from hydrogen peroxide in a patient with acatalasemia. Anesthesiology 101, 247-248.
• 30)  Quan, F., Korneluk, R.G., Tropak, M.B. and Gravel, R.A. (1986) Isolation and characterization of the human catalase gene. Nucleic Acids Res. 14, 5321-5335.
• 31)  Bell, G.I., Najarian, R.C., Mullenbach, G.T. and Hallewell, R.A. (1986) cDNA sequence coding for human kidney catalase. Nucleic Acids Res. 14, 5561-5562.
• 32)  Wen, J.K., Osumi, T., Hashimoto, T. and Ogata, M. (1990) Molecular analysis of human acatalasemia. Identification of a splicing mutation. J. Mol. Biol. 211, 383-393.
• 33)  Hirono, A., Sasaya-Hamada, F., Kanno, H., Fujii, H., Yoshida, T. and Miwa, S. (1995) A novel human catalase mutation (358 T-->del) causing Japanese-type acatalasemia. Blood Cells Mol. Dis. 21, 232-234.
• 34)  Góth, L., Shemirani, A. and Kalmár, T. (2000) A novel catalase mutation (a GA insertion) causes the Hungarian type of acatalasemia. Blood Cells Mol. Dis. 26, 151-154.
• 35)  Ogata, M., Hayashi, S. and Takahara, S. (1971) Estimation of the frequency of the recessive gene of acatalasemia in Japan. Acta Med. Okayama 25, 193-198.
• 36)  Chen, S., Francioli, L.C., Goodrich, J.K., Collins, R.L., Kanai, M., Wang, Q. et al. (2024) A genomic mutational{} constraint map using variation in 76,156 human genomes. Nature 625, 92-100.
• 37)  Góth, L. and Nagy, T. (2012) Acatalasemia and diabetes mellitus. Arch. Biochem. Biophys. 525, 195-200.
• 38)  Yamada, Y., Sakuma, J., Takeuchi, I., Yasukochi, Y., Kato, K., Oguri, M. et al. (2017) Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies. Oncotarget 8, 80492-80505.

Related Articles

• Takahara, S. (1951) Acatalasemia (lack of catalase in blood) and an oral progressive gangrene. Proc. Jpn. Acad. 27, 295-301.

Appendices

[From Proc. Jpn. Acad., Vol. 27 No. 6, pp. 295-301 (1951)]

Profile

Mizuo Ando was born in Switzerland in 1975 and later grew up in Hokkaido, Japan. He graduated from the University of Tokyo School of Medicine in 2000. He majored in otorhinolaryngology and trained at Teikyo University Ichihara Hospital, the University of Tokyo Hospital, and the National Cancer Center Hospital. He received his PhD degree in 2014 for the discovery of novel cancer-related genes by comprehensive genomic analysis of head and neck cancer and their functional validation. He continued his research on cancer genomics and epigenomics while working as a head and neck surgeon, and he studied at University of California San Diego from 2016 to 2017. In 2020, he was appointed as a professor of Otorhinolaryngology-Head and Neck Surgery at Okayama University. At Okayama University, he was exposed to the significant work of Emeritus Professor Shigeo Takahara on human genetics and had the opportunity to write a review of Dr. Takahara's pioneering research on acatalasemia with Dr. K. Fukushima and Emeritus Professor K. Nishizaki.