Commentary on the Mutation Spectrum of and Founder Effects Affecting the PTS Gene in East-Asian Populations

COMMENTARY

Commentary on the mutation spectrum of and founder effects affecting the PTS gene in East-Asian populations

Haruo Shintaku

Journal of Human Genetics (2012) 57, 159–160; doi:10.1038/jhg.2011.153; published online 16 February 2012

etrahydrobiopterin (BH4) deficiency is a gene mutations of all five enzymes have been 156 families, Japanese: 6 families, South Kor- T rare disorder affecting phenylalanine reported.3 The incidence of BH4 deficiency is ean: 7 families, Thai: 3 families and Filipinos: 4 metabolism in the liver and neurotransmit- at 1 in 1 000 000, except that in Taiwanese families) and total of 352 mutations were ters biosynthesis in the brain. In 1975, Smith (much higher than that in Japanese and in analyzed. Mutations found in these patients et al.1 first reported these patients as ‘atypical Caucasians).5,6 Liu et al.7 reported that the were strongly linked to a microsatellite marker, phenylketonuria (PKU)’. Patients with BH4 BH4-deficient HPA was estimated to make up D11S1347. Among these, five mutations were deficiency appear normal at birth, but experi- around 30% of the Chinese population in the most common in East Asia. These muta- ence symptoms such as intellectual disability, Taiwan suffering from HPA, which is much tions were not located in CpG hot spots. These progressive problems with development, higher than in Caucasian populations (1.5– results indicate that each of the common movement disorders, difficulty swallowing, 2% of HPA). In Taiwan approximately 86% mutations came from a single ancestor. The seizures and behavioral problems. Bartho- of BH4-deficient HPA in the Chinese popula- authors suggested that the founders were lome´ et al.2 reported that the neurological tion was found to be caused by PTPS defi- ancient Chinese of Mainland China. In con- signs in these patients were treatable by ciency, although it is the most common form trast, Okinawan people in Japan and Filipinos the oral administration of the neurotransmit- of BH4 deficiency in the world. each showed a unique mutation in PTS.9 This ter precursors 3,4-dihydroxyphenylalanine BH4 deficiency has been diagnosed in result suggests that these two separated regions (L-DOPA) and 5-hydroxytryptophan (5- patients with HPA by neonatal mass screen- had their own founders. HTP), both of which cross the blood–brain ing based on BH4 oral loading tests, analysis What key concepts and lessons can be barrier. Shintaku et al.3 recommended that of urinary or serum pteridines and measure- derived from this study? this treatment be started within 2 months of ment of DHPR activity in the blood from a First, the author investigated PTPS- birth to help prevent neurological damage. Guthrie card. BH4 deficiency without treat- deficiency patients of the Han people in Therefore, the expression ‘BH4 deficiency’ ment causes combined symptoms of HPA Taiwan, Mainland China and Malaysia in should be used rather than the terms ‘atypical and neurotransmitter (dopamine, norepi- this study. Patients of other countries such PKU’ or ‘malignant hyperphenylalaninemia nephrine, epinephrine and serotonin) defi- as Japan, South Korea and Philippine were (HPA)’.4 ciency, such as red hair, psychomotor also analyzed. The results indicate that BH4 is an essential cofactor in the retardation and progressive neurological dete- mutations of the PTS gene in East Asia enzymatic hydroxylation of three aromatic rioration, as mentioned before. Treatment of were within the area of D11S1347, which amino acids (phenylalanine, tyrosine and BH4 deficiencies consists of BH4 supplemen- is important and useful in diagnosing tryptophan). BH4 is synthesized from guano- tation (2–20 mg kgÀ1 per day) or diet to patients with PTPS-deficiency in East Asia. sine triphosphate (GTP) catalyzed by GTP control the blood phenylalanine concentration Second, five common mutations were cyclohydrolase I, 6-pyruvoyl-tetrahydropterin andreplacementtherapywithneurotransmit- found in patients of Mainland China on the synthase (PTPS) and sepiapterin reductase. In ters precursors (L-DOPA/CarbiDOPA and coast and those of the Han people in other aromatic amino acids hydoxylating sys- 5-HTP), and supplements of folinic acid in countries. Some of those mutations were tem, BH4 is regenerated by pterin-4a-carbino- DHPR deficiency.5 found only in East Asia. It is better to collect lamine dehydratase and dihydropteridine In previous issue of the Journal,Chiuet al.8 the information of patients in inland Main- reductase. (DHPR).5 They all follow an auto- investigated mutations in the patients with land China, the Mongolian people and other somal-recessive mode of inheritance and the PTPS (gene symbol: PTS) deficiency in countries to investigate the origin of those East-Asian populations and increased our mutations. understanding of the mutation spectrum Third, the author reports that the preva- H Shintaku is at the Department of Pediatrics, Osaka and founder effects affecting the PTS gene lence rate of HPA in each East-Asian country City University Graduate School of Medicine, Osaka, 6 Japan. in East-Asian populations. The patients were was lower than that of the Caucasian E-mail: [email protected] from 176 families (Han Chinese populations: population. However, the incidence of BH4 Commentary 160

deficiency among HPA in East-Asian countries to screen of PTPS deficiency in East Asia. 4 Blau, N., Thoÿ, B., Cotton, R. G. H. & Hyland, K. In The was higher than that of the rest of the world. It These mutations were mainly observed in Metabolic Basis of Inherited Diseases (Scriver, ed). 1725–1776 (McGraw Hill, London, 2000). is possible that several founder events occurred patients of the Han people. The high preva- 5 Shintaku, H. Disorders of tetrahydrobiopterin metabolism in the Han people (or other neighboring lencerateofPTPSdeficiencyintheHan and their treatment. Curr. Drug Metab. 3, 123–131 (2002). peoples) and those mutations spread over people would explain the high incident rate 6Tho¨ny, B. & Blau, N. Mutations in the BH4-metabolizing other areas along with the immigration of of this disorder in East Asia. genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin the Han people. It would be of interest to synthase, sepiapterin reductase, carbinolamine-4a- dehydratase, and dihydropteridine reductase. Hum. compare mutations of the PTS gene in East Mutat. 27, 870–878 (2006). Asia and in other parts of the world, for it may 7 Liu, T. T., Chiang, S. H., Wu, S. J. & Hsiao, K. J. reveal early human migrations in ancient 1 Smith, I., Clayton, B. E. & Wolff, O. H. New variant of Tetrahydrobiopterin-deficient hyperphenylalaninemia in phenylketonuria with progressive neurological illness the Chinese. Clin. Chim. Acta. 313, 157–169 (2001). times. The patients of the two isolated regions unresponsive to phenylalanine restriction. Lancet 1, 8 Chiu, Y. H., Chang, Y.- C., Chang, Y.- H., Niu, D.- M., (Okinawa islands in Japan and the Philip- 1108–1111 (1975). Yang, Y.- L., Ye, J. et al. Mutation spectrum of 2 Bartholome´, K., Byrd, D. J., Kaufman, S. & Milstien, S. and founder effects affecting the PTS gene in pines) showed other types of mutations Atypical phenylketonuria with normal phenylalanine East-Asian populations. J. Hum. Genet. 57, 145–152 9 in the PTS gene. It was suggested that other hydroxylase and dihydropteridine reductase activity (2012). founder events have occurred in those areas. in vitro. Pediatrics 59, 757–761 (1977). 9 Imamura, T., Okano, Y., Shintaku, H., Hase, Y. & Isshiki, 3 Shintaku, H., Asada, M. & Sawada, Y. Diagnosis and G. Molecular characterization of 6-pyruvoyl-tetrahydrop- In conclusion, this study represents the treatment of 6-pyruvoyl-tetrahydropterin synthase defi- terin synthase deficiency in Japanese patients. J. Hum. usefulness of microsatellite marker, D11S1347 ciency. Brain Dev. 22, S118–S121 (2000). Genet. 44, 163–168 (1999).

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