Molecular Genetics and Metabolism 105 (2012) 551–552

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Molecular Genetics and Metabolism

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Commentary

A tribute to Keiko Kobayashi and her work on citrin deficiency

Meow-Keong ThongGenetics & Metabolism Unit, Department of Pediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia

E-mail address: thongmk@um.edu.my.

1096-7192/$ – see front matter © 2012 Elsevier Inc. Alldoi:10.1016/j.ymgme.2012.01.003

a r t i c l e i n f o NICCD and the benefits included avoidance of extensive and potentially

Article history:

Received 3 January 2012Accepted 3 January 2012Available online 10 January 2012

risky investigations in infants with neonatal cholestasis, provision of ap-propriate dietary management and genetic counseling, and long termhealth surveillance [5]. In many centers in Asia and elsewhere, NICCDis a condition to be excluded early in infants with prolonged cholestasisand this had led to a change in pediatric practice.

The awareness that biochemical changesmay be absent inNICCD ledto the need to develop a cost effective technique formolecular diagnosis

Associate Professor Keiko Kobayashi from Kagoshima University,

together with Professor Takeyori Saheki, was the pioneer in thefield of research on citrin deficiency.

Since hermedical graduation and subsequent obtainment of her PhDat Tokushima University, Japan, Associate Professor Kobayashi had beeninvolved in the field of biochemistry and molecular genetics—her earlyinterest had been in the study of the molecular mechanism on the het-erogeneous distribution of argininosuccinate synthetase in the liver oftype II citrullinemia in 1986 [1]. This led to further research in the1990s culminating in the characterization of the gene involved in citrindeficiency [2]. Together with Professor Saheki and their collaborators,they identified two phenotypes of citrin deficiency: citrullinemia type II(CTLN2) andneonatal intrahepatic cholestasis caused by citrin deficiency(NICCD) anddelineated the involvement of the aspartate–glutamate car-rier for urea synthesis and maintenance of the urea cycle [3].

She and her teamhadworked on all aspects of citrin deficiency, rang-ing from the basic sciences to epidemiology aspects aswell as the clinicaland molecular heterogeneity of the condition [4–6], development ofmouse models [7] as well as formulating the treatment options for citrindeficiency [8].

Associate Professor Kobayashi and her team faced a number ofchallenges. First, there was a perception that citrin deficiency wasfound mostly in Japanese and East Asians only. However, as a resultof research of this condition on a global basis, citrin deficiency isnow recognized as a pan-ethnic disorder [9].

Secondly, as the biochemical changes of NICCD often normalized by6 months of age, molecular diagnosis was the main option available fora definitive diagnosis. She received numerous requests from many de-veloping countries, particularly from Asia who sought her help in mak-ing the molecular diagnosis of this condition. Despite many limitations,she always managed to answer her email correspondence promptlywith her offers to help out. As prolonged cholestasis is a common con-dition in Asian infants, many babies were subjected to liver biopsyand laparotomy to exclude biliary atresia. As a result of the availabilityof genetic testing of the SLC25A13, this led to the earlier diagnosis of

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in the population. This approach has been taken to the next stepwhere-bymass screening of commonmutations found in the population is nowdeveloped. This can potentially be used in expanded newborn screeningprograms [10,11].

In addition to the probands, other familymemberswith NICCDwereidentified using this approach. Undoubtedly, many liveswere saved as aresult. Prenatal diagnosis for this condition had also been successfullycarried out [12].

Throughout the past decade, many medical geneticists, particular-ly those from third world countries with limited resources, had foundAssociate Professor Kobayashi to be pleasant, helpful and compas-sionate. She was ever constructive in her comments and carefulabout the accuracy of clinical and laboratory data. It was truly educa-tional and an eye-opening experience to collaborate with her and herteam. Not many people were aware she had been unwell for sometime. In person, she was always humble, encouraging and positive.

In honor of her work and achievements, the Asian Society forInherited Metabolic Diseases (ASIMD) during the First Asian Congressfor Inherited Metabolic Diseases (ACIMD), in Fukuoka Japan, 7th–10thMarch 2010 organized a symposium on ‘citrin deficiency’where severalkey researchers were invited to give talks. In December 2010, the Asia-Pacific Society of Human Genetics organized a workshop during the 9thAsia-Pacific Conference on Human Genetics entitled AASPP Symposiumon Citrin Deficiency on the 2nd December 2010. She delivered the firstlecture entitled “SLC25A13 Mutations/Variations in Citrin Deficiency:Frequency and Distribution”.

She passed away peacefully several weeks later at the age of 63 yearsold. She had touched countless lives of her patients, colleagues and peers.She had inspired a generation of young geneticists particularly from Japanand Asia that muchwork remains to be done, both in citrin deficiency, inparticular and in inheritedmetabolic disorders, in general. Shewas a ded-icated teacher, mentor and friend and shall be greatly missed.

References

[1] K. Kobayashi, T. Saheki, Y. Imamura, T. Noda, I. Inoue, S. Matuo, S. Hagihara, H.Nomiyama, Y. Jinno, K. Shimada, Messenger RNA coding for argininosuccinatesynthetase in citrullinemia, Am. J. Hum. Genet. 38 (1986) 667–680.

552 M.-K. Thong / Molecular Genetics and Metabolism 105 (2012) 551–552

[2] K. Kobayashi, D.S. Sinasac,M. Iijima, A.P. Boright, L. Begum, J.R. Lee, T. Yasuda, S. Ikeda, R.Hirano, H. Terazono, M.A. Crackower, I. Kondo, L.C. Tsui, S.W. Scherer, T. Saheki, Thegene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrialcarrier protein, Nat. Genet. 22 (1999) 159–163.

[3] T. Saheki, K. Kobayashi, M. Iijima,M. Horiuchi, L. Begum,M.A. Jalil, M.X. Li, Y.B. Lu, M.Ushikai, A. Tabata, M. Moriyama, K.J. Hsiao, Y. Yang, Adult-onset type II citrullinemiaand idiopathic neonatal hepatitis caused by citrin deficiency: involvement of theaspartate–glutamate carrier for urea synthesis and maintenance of the urea cycle,Mol. Genet. Metab. 81 (Suppl 1) (2004) S20–S26.

[4] Y.Z. Song, M. Deng, F.P. Chen, F. Wen, L. Guo, S.L. Cao, J. Gong, H. Xu, G.Y. Jiang, L.Zhong, K. Kobayashi, T. Saheki, Z.N. Wang, Genotypic and phenotypic features ofcitrin deficiency: five-year experience in a Chinese pediatric center, Int. J. Mol.Med. 28 (2011) 33–40.

[5] M.K. Thong, C.C. Boey, J.S. Sheng, M. Ushikai, K. Kobayashi, Neonatal intrahepaticcholestasis caused by citrin deficiency in two Malaysian siblings: outcome at oneyear of life, Singapore Med. J. 51 (2010) e12–e14.

[6] A. Tabata, J.S. Sheng, M. Ushikai, Y.Z. Song, H.Z. Gao, Y.B. Lu, F. Okumura, M. Iijima,K. Mutoh, S. Kishida, T. Saheki, K. Kobayashi, Identification of 13 novel mutationsincluding a retrotransposal insertion in SLC25A13 gene and frequency of 30 mu-tations found in patients with citrin deficiency, J. Hum. Genet. 53 (2008)534–545.

[7] T. Saheki, K. Inoue, H. Ono, A. Tushima, N. Katsura, M. Yokogawa, Y. Yoshidumi, T.Kuhara, M. Ohse, K. Eto, T. Kadowaki, D.S. Sinasac, K. Kobayashi, Metabolomic analysis

reveals hepatic metabolite perturbations in citrin/mitochondrial glycerol-3-phosphatedehydrogenase double-knockout mice, a model of human citrin deficiency, Mol.Genet. Metab. 104 (2011) 492–500.

[8] M. Yazaki, S. Ikeda, K. Kobayashi, T. Saheki, Therapeutic approaches for patientswith adult-onset type II citrullinemia (CTLN2): effectiveness of treatment withlow-carbohydrate diet and sodium pyruvate, Rinsho Shinkeigaku 50 (2010)844–847.

[9] D. Dimmock, B. Miranda, C. Dionisi-Vici, J. Wang, S. Kleppe, G. fiermonte, R. Bai, B.Hainline, A. Hamosh, W.E. O’Brien, F. Scagila, L.J. Wong, Citrin deficiency, a per-plexing global disorder, Mol. Genet. Metab. 96 (2009) 44–49.

[10] A. Tamamori, A. Fujimoto, Y. Okano, K. Kobayashi, T. Saheki, Y. Tagami, H. Takei, Y.Shigematsu, I. Hata, H. Ozaki, D. Tokuhara, Y. Nishimura, T. Yorifuji, N. Igarashi, T.Ohura, T. Shimizu, K. Inui, N. Sakai, D. Abukawa, T. Miyakawa, M. Matsumori, K.Ban, H. Kaneko, T. Yamano, Effects of citrin deficiency in the perinatal period: feasi-bility of newborn mass screening for citrin deficiency, Pediatr. Res. 56 (2004)608–614.

[11] K. Kobayashi, L.Y. Bang, L.M. Xian, I. Nishi, K.J. Hsiao, K. Choeh, Y. Yang, W.L. Hwu,J.K. Reichardt, F. Palmieri, Y. Okano, T. Saheki, Screening of nine SLC25A13 muta-tions: their frequency in patients with citrin deficiency and high carrier rates inAsian populations, Mol. Genet. Metab. 80 (2003) 356–359.

[12] X.J. Zhao, X.M. Tang, Q.B. Zha, S.S. Shi, Y.Z. Song, X.M. Xiao, Prenatal diagnosis ofcitrin deficiency in a Chinese family with a fatal proband, Tohoku J. Exp. Med.225 (2011) 273–276.