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J Zhejiang Univ (Med Sci)  2018, Vol. 47 Issue (3): 219-226    DOI: 10.3785/j.issn.1008-9292.2018.06.01
    
Research progress on phenotype and genotype of hyperphenylalaninemia
CHEN Ting1(),ZHAO Zhengyan2,JIANG Pingping3,SHU Qiang1,*()
1. Department of Cardiovascular and Thoracic Surgery, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
2. Department of Genetics and Metabolic Diseases, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
3. Institute of Genetics, Zhejiang University, Hangzhou 310058, China
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Abstract  

Hyperphenylalaninemia(HPA), an autosomal recessive disease, is the most common inborn error of amino acid metabolism, caused by the deficiency of phenylalanine hydroxylase(PAH) or tetrahydrobiopterin(BH4) which induced by mutations of genes. The accumulation of the clinical database and genetic information will enhance the development of novel personalized medicine and to provide more accurate and timely diagnostic and therapeutic approaches for HPA. This paper summarizes the correlations between HPA metabolism and PAH, BH4, pathogenic genes and their distributions in HPA, as well as the phenotypes and genotypes of HPA, so as to provide reference for personalized medicine for HPA.



Key wordsPhenylketonurias/genetics      Phenylalanine hydroxylase      Biopterin/metabolism      Phenotype      Genotype      Review     
Received: 23 March 2018      Published: 18 September 2018
CLC:  R722.11  
Corresponding Authors: SHU Qiang     E-mail: 11718194@zju.edu.cn;shuqiang@zju.edu.cn
Cite this article:

CHEN Ting,ZHAO Zhengyan,JIANG Pingping,SHU Qiang. Research progress on phenotype and genotype of hyperphenylalaninemia. J Zhejiang Univ (Med Sci), 2018, 47(3): 219-226.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2018.06.01     OR     http://www.zjujournals.com/med/Y2018/V47/I3/219


高苯丙氨酸血症表型与基因型研究进展

高苯丙氨酸血症(HPA)是最常见的先天性、常染色体隐性遗传的氨基酸代谢病,由苯丙氨酸羟化酶(PAH)或辅酶四氢生物蝶呤(BH4)缺乏所致,并受基因调控。HPA临床数据与基因信息是疾病诊断、治疗和预防的宝贵资源,信息的有效积累将推动HPA诊治更加及时和准确,为制订个性化的诊疗方案提供新手段。本文总结了HPA代谢途径与蛋白PAH和BH4的关联、HPA的致病基因及其分布、HPA的基因型与表型的关系,为HPA的个性化治疗提供参考。


关键词: 苯丙酮尿症/遗传学,  苯丙氨酸羟化酶,  生物蝶呤/代谢,  表型,  基因型,  综述 
Fig 1 Phenylalanine metabolism with phenylalanine hydroxylase and tetrahydrobiopterin
Fig 2 Distribution of mutations across the PAH gene (data come from PAHvdb)
[1]   中华医学会儿科学分会内分泌遗传代谢学组, 中华预防医学会出生缺陷预防与控制专业委员会新生儿筛查学组 . 高苯丙氨酸血症的诊治共识[J]. 中华儿科杂志, 2014, 52 (6): 420- 425
Group of Hereditary Metabolic Endocrinology, Chinese Pediatric Society of Chinese Medical Association , Neonatal Screening Group of the Committees for Prevention and Control of Birth Defects, Chinese Preventive Medicine Association . Expert consensus on hyperphenylalaninemia[J]. Chinese Journal of Pediatrics, 2014, 52 (6): 420- 425
doi: 10.3760/cma.j.issn.0578-1310.2014.06.005
[2]   叶军, 邱文娟, 韩连书 et al. 新生儿筛查诊断的223例高苯丙氨酸血症的诊治及随访[J]. 中华预防医学杂志, 2007, 41 (3): 189- 192
YE Jun , QIU Wenjuan , HAN Lianshu et al. Diagnosis, treatment and long-term following up of 223 patients with hyperphenylalaninemia detected by neonatal screening programs[J]. Chinese Journal of Preventive Medicine, 2007, 41 (3): 189- 192
doi: 10.3760/j:issn:0253-9624.2007.03.009
[3]   KOBE B , JENNINGS I G , HOUSE C M et al. Structural basis of autoregulation of phenylalanine hydroxylase[J]. Nat Struct Biol, 1999, 6 (5): 442- 448
doi: 10.1038/8247
[4]   ARTURO E C , GUPTA K , HéROUX A et al. First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer[J]. Proc Natl Acad Sci U S A, 2016, 113 (9): 2394- 2399
doi: 10.1073/pnas.1516967113
[5]   GERSTING S W , KEMTER K F , STAUDIGL M et al. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability[J]. Am J Hum Genet, 2008, 83 (1): 5- 17
doi: 10.1016/j.ajhg.2008.05.013
[6]   BLAU N , SHEN N , CARDUCCI C . Molecular genetics and diagnosis of phenylketonuria:state of the art[J]. Expert Rev Mol Diagn, 2014, 14 (6): 655- 671
doi: 10.1586/14737159.2014.923760
[7]   WERNER E R , BLAU N , TH?NY B . Tetrahydrobiopterin:biochemistry and pathophysiology[J]. Biochem J, 2011, 438 (3): 397- 414
[8]   叶军, 邱文娟, 韩连书 et al. 398例新生儿各型高苯丙氨酸血症的研究及26年诊治经验[J]. 中华围产医学杂志, 2008, 11 (6): 382- 387
YE Jun , QIU Wenjuan , HAN Lianshu et al. Study on 398 neonates with various types of hyperphenylalaninemia detected by neonatal screening program and 26 year-experiences of diagnosis and treatment for hyperphenylalaninemia[J]. Chinese Journal of Perinatal Medicine, 2008, 11 (6): 382- 387
doi: 10.3760/cma.j.issn.1007-9408.2008.06.006
[9]   王秀利, 禇英, 顾茂胜 et al. 2003年至2015年徐州市新生儿高苯丙氨酸血症筛查及治疗效果[J]. 中华围产医学杂志, 2016, 19 (8): 596- 602
WANG Xiuli , CHU Ying , GU Maosheng et al. Analysis of neonatal hyperphenylalaninemia screening and therapeutic effect in Xuzhou from 2003 to 2015[J]. Chinese Journal of Perinatal Medicine, 2016, 19 (8): 596- 602
doi: 10.3760/cma.j.issn.1007-9408.2016.08.009
[10]   范歆, 陈少科, 林彩娟 et al. 广西地区高苯丙氨酸血症发病情况分析[J]. 广西医科大学学报, 2012, 29 (4): 579- 581
FAN Xin , CHEN Shaoke , LIN Caijuan et al. Analysis of the occurance of hyperphenylalaninemia in Guangxi Province[J]. Journal of Guangxi Medical University, 2012, 29 (4): 579- 581
doi: 10.3969/j.issn.1005-930X.2012.04.034
[11]   孙云, 蒋涛, 张菁菁 et al. 南京地区新生儿高苯丙氨酸血症筛查27年回顾[J]. 中华围产医学杂志, 2013, 16 (6): 357- 361
SUN Yun , JIANG Tao , ZHANG Jingjing et al. Neonatal hyperphenylalaninemia screening from 1985 to 2012 in Nanjing:a retrospective analysis of 27 years[J]. Chinese Journal of Perinatal Medicine, 2013, 16 (6): 357- 361
doi: 10.3760/cma.j.issn.1007-9408.2013.06.009
[12]   ZHU T , YE J , HAN L et al. The predictive value of genetic analyses in the diagnosis of tetrahydrobiopterin(BH4)-responsiveness in Chinese phenylalanine hydroxylase deficiency patients[J]. Sci Rep, 2017, 7 (1): 6762
doi: 10.1038/s41598-017-06462-y
[13]   JERVIS G A . Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidizing system[J]. Proc Soc Exp Biol Med, 1953, 82 (3): 514- 515
[14]   WOO S L , LIDSKY A S , GVTTLER F et al. Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria[J]. Nature, 1983, 306 (5939): 151- 155
doi: 10.1038/306151a0
[15]   ROBSON K J , BEATTIE W , JAMES R J et al. Sequence comparison of rat liver phenylalanine hydroxylase and its cDNA clones[J]. Biochemistry, 1984, 23 (24): 5671- 5675
doi: 10.1021/bi00319a001
[16]   DILELLA A G , MARVIT J , LIDSKY A S et al. Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria[J]. Nature, 1986, 322 (6082): 799- 803
doi: 10.1038/322799a0
[17]   DILELLA A G , MARVIT J , BRAYTON K et al. An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2[J]. Nature, 1987, 327 (6120): 333- 336
doi: 10.1038/327333a0
[18]   KONECKI D S , WANG Y , TREFZ F K et al. Structural characterization of the 5' regions of the human phenylalanine hydroxylase gene[J]. Biochemistry, 1992, 31 (35): 8363- 8368
doi: 10.1021/bi00150a033
[19]   PAHvdb[DB/OL].[2018-02-20] http://www.biopku.org/home/pah.asp.
[20]   LI N , JIA H , LIU Z et al. Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing[J]. Sci Rep, 2015, 5 15769
doi: 10.1038/srep15769
[21]   LIU N , HUANG Q , LI Q et al. Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China[J]. BMC Med Genet, 2017, 18 (1): 108
doi: 10.1186/s12881-017-0467-7
[22]   CHIEN Y H , CHIANG S C , HUANG A et al. Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation[J]. Hum Mutat, 2004, 23 (2): 206
[23]   BIODEFdb[DB/OL].[2018-02-20] http://www.biopku.org/home/biodef.asp.
[24]   LIU T T , CHIANG S H , WU S J et al. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese[J]. Clin Chim Acta, 2001, 313 (1-2): 157- 169
doi: 10.1016/S0009-8981(01)00669-6
[25]   YE J , YANG Y , YU W et al. Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China:results of a retrospective, multicentre study[J]. J Inherit Metab Dis, 2013, 36 (5): 893- 901
doi: 10.1007/s10545-012-9550-6
[26]   HIEN Y H , CHIANG S C , HUANG A et al. Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations[J]. J Inherit Metab Dis, 2001, 24 (8): 815- 823
doi: 10.1023/A:1013984022994
[27]   LIU T T , CHANG Y H , CHIANG S H et al. Identification of three novel 6-pyruvoyl-tetrahydropterin synthase gene mutations(226C > T, IVS3+1G > A, 116-119delTGTT) in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency[J]. Hum Mutat, 2001, 18 (1): 83
[28]   HAN B , ZOU H , HAN B et al. Diagnosis, treatment and follow-up of patients with tetrahydrobiopterin deficiency in Shandong province, China[J]. Brain Dev, 2015, 37 (6): 592- 598
doi: 10.1016/j.braindev.2014.09.008
[29]   叶军 . 高苯丙氨酸血症的诊治及研究进展[J]. 临床儿科杂志, 2010, 28 (2): 197- 200
YE Jun . The development in diagnosis treatment and gene study of hyperphenylalaninemia[J]. Journal of Clinical Pediatrics, 2010, 28 (2): 197- 200
doi: 10.3969/j.issn.1000-3606.2010.02.026
[30]   CHIU Y H , CHANG Y C , CHANG Y H et al. Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations[J]. J Hum Genet, 2012, 57 (2): 145- 152
doi: 10.1038/jhg.2011.146
[31]   ANIKSTER Y , HAACK T B , VILBOUX T et al. Biallelic mutations in DNAJC12 cause hyperphenylalaninemia, dystonia, and intellectual disability[J]. Am J Hum Genet, 2017, 100 (2): 257- 266
doi: 10.1016/j.ajhg.2017.01.002
[32]   VAN SPRONSEN F J , HIMMELREICH N , RÜFENACHT V et al. Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia:from attention deficit to severe dystonia and intellectual disability[J]. J Med Genet, 2017,
[33]   BIOPKUdb[DB/OL].[2018-02-20] http://www.biopku.org/home/biopku.asp.
[34]   SCRIVERC R . The PAH gene, phenylketonuria, and a paradigm shift[J]. Hum Mutat, 2007, 28 (9): 831- 845
doi: 10.1002/(ISSN)1098-1004
[35]   BLAU N . Genetics of phenylketonuria:then and now[J]. Human Mutation, 2016, 37 (6): 508- 515
doi: 10.1002/humu.22980
[36]   WETTSTEIN S , UNDERHAUG J , PEREZ B et al. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria[J]. Eur J Hum Genet, 2015, 23 (3): 302- 309
doi: 10.1038/ejhg.2014.114
[37]   KURE S , HOU D C , OHURA T et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency[J]. J Pediatr, 1999, 135 (3): 375- 378
doi: 10.1016/S0022-3476(99)70138-1
[38]   BERNEGGER C , BLAU N . High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias:a study of 1, 919 patients observed from 1988 to 2002[J]. Mol Genet Metab, 2002, 77 (4): 304- 313
doi: 10.1016/S1096-7192(02)00171-3
[39]   FIEGE B , BLAU N . Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria[J]. J Pediatr, 2007, 150 (6): 627- 630
doi: 10.1016/j.jpeds.2007.02.017
[40]   MATALON R , MICHALS-MATALON K , KOCH R et al. Response of patients with phenylketonuria in the US to tetrahydrobiopterin[J]. Mol Genet Metab, 2005, 86 (Suppl 1): S17- S21
[41]   MITCHELL J J , WILCKEN B , ALEXANDER I et al. Tetrahydrobiopterin-responsive phenylketonuria:the New South Wales experience[J]. Mol Genet Metab, 2005, 86 (Suppl 1): S81- 85
[42]   邹卉, 韩炳娟, 卜晓萍 et al. 山东省高苯丙氨酸血症分型及治疗效果评价与基因分析[J]. 中国儿童保健杂志, 2012, 20 (3): 208- 210
ZOU Hui , HAN Bingjuan , PU Xiaoping et al. Classification and treatment effect evaluation and genetic analysis of hyperphenylalaninemia in Shandong[J]. Chinese Journal of Child Health Care, 2012, 20 (3): 208- 210
[43]   TRUNZO R , SANTACROCE R , SHEN N et al. In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU[J]. Gene, 2016, 594 (1): 138- 143
doi: 10.1016/j.gene.2016.09.015
[44]   叶军, 邱文娟, 韩连书 et al. 四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症的临床和基因检测[J]. 中国实用儿科杂志, 2005, 20 (12): 718- 720
YE Jun , QIU Wenjuan , HAN Lianshu et al. Clinical and genetic analysis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency[J]. Journal of Clinical Pediatrics, 2005, 20 (12): 718- 720
doi: 10.3969/j.issn.1005-2224.2005.12.009
[45]   TAO J , LI N , JIA H et al. Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria[J]. Pediatr Res, 2015, 78 (6): 691- 699
doi: 10.1038/pr.2015.167
[46]   SHINTAKU H , KURE S , OHURA T et al. Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene[J]. Pediatr Res, 2004, 55 (3): 425- 430
doi: 10.1203/01.PDR.0000111283.91564.7E
[47]   杨凌, 张知新, 叶军 et al. 四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症在我国南北地区差异的临床初步研究[J]. 中华医学遗传学杂志, 2007, 24 (3): 310- 313
YANG Lin , ZHANG Zhixin , YE Jun et al. Clinical study of tetrahydrobiopterin responsive phenylalanine hydroxylase deficiency in southern and northern Chinese patients[J]. Chinese Journal of Medical Genetics, 2007, 24 (3): 310- 313
doi: 10.3760/j.issn:1003-9406.2007.03.016
[48]   沈明, 喻唯民, 杨凌 et al. 四氢生物蝶呤缺乏症的临床研究[J]. 中日友好医院学报, 2002, 16 (1): 8- 10
SHEN Ming , YU Weimin , YANG Lin et al. Clinical studies of patients with tetrahydrobiopterin deficiency[J]. Journal of China-Japan Friendship Hospital, 2002, 16 (1): 8- 10
doi: 10.3969/j.issn.1001-0025.2002.01.002
[49]   PNDdb[DB/OL].[2018-02-20] http://www.biopku.org/home/pnddb.asp.
[50]   刘宁, 赵德华, 李晓乐 et al. PTPS基因检测在6丙酮酰四氢蝶呤合成酶缺乏症出生后诊断和产前诊断中的应用[J]. 中华妇产科杂志, 2016, 51 (12): 890- 894
LIU Ning , ZHAO Dehua , LI Xiaole et al. PTPS gene analysis and prenatal diagnosis in patients with 6-pyruvoyl-tetra hydropterin synthase deficiency[J]. Chinese Journal of Obstetrics and Gynecology, 2016, 51 (12): 890- 894
doi: 10.3760/cma.j.issn.0529-567x.2016.12.003
[51]   LI N , YU P , RAO B et al. Molecular genetics of tetrahydrobiopterin deficiency in Chinese patients[J]. J Pediatr Endocrinol Metab, 2018, 31 (8): 911- 916
doi: 10.1515/jpem-2018-0037
[52]   叶军, 陈瑞冠.6-丙酮酰四氢蝶呤合成酶(PTPS)缺乏病9例分析[C]//第一届全国新生儿疾病筛查学术交流会论文集.贵阳: 中华预防医学会儿童保健分会新生儿筛查学组, 2007: 51.
YE Jun, CHEN Ruiguan. Analysis of nine cases of 6-pyruvoyl tetrahydropterinsynthase deficiency[C]//Proceedings of the National Conference on Neonates Diseases Screening. Guiyang: Neonatal Screening Group, Society of Child Health, Chinese Preventive Medicine Association, 2007: 51. (in Chinese)
[53]   叶军, 刘晓青, 黄晓东 et al. 中国南方四氢生物蝶呤缺乏症筛查、临床及基因突变的系列研究[J]. 中华医学遗传学杂志, 2001, 18 (2): 92- 95
YE Jun , LIU Xiaoqing , HUANG Xiaodong et al. Studies on neonatal screening, clinical and gene analysis for tetrahydrobiopterin deficiency in Southern Chinese[J]. Chinese Journal of Medical Genetics, 2001, 18 (2): 92- 95
doi: 10.3760/j.issn:1003-9406.2001.02.003
[54]   KHATAMI S , DEHNABEH S R , ZEINALI S et al. Four years of diagnostic challenges with tetrahydrobiopterin deficiencies in iranian patients[J]. JIMD Rep, 2017, 32 7- 14
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