目的 了解四川省部分地区高苯丙氨酸血症(HPA)患儿基因突变情况,构建本地区HPA相关基因突变谱,为患儿基因诊断、产前诊断及遗传咨询提供依据。方法 采用第二代测序技术对43例HPA患儿的PAH、PTS、QDPR、PCBD1、SPR及GCH1基因进行分析。结果 检出PAH基因突变35例,PTS基因突变8例。占前3位的PAH高频突变为p.R243Q、p.R241C及p.Ex6-96A>G,高频突变的区域为第7外显子,包含了28个突变(39.4%)。p.G272V未见报道。PTS基因的高频突变位点为p.P87S、p.Y27Rfs*8、p.D96N及p.V56M,高频突变区域为第5外显子,包含了8个突变(50.0%)。p.T58R未见报道。结论 本研究初步构建了四川省部分地区HPA相关基因的突变谱,在PAH和PTS基因上各发现1个新突变,为本地区HPA患儿的基因诊断和遗传咨询提供了依据。
Abstract
Objective To investigate the characteristics of gene mutations in children with hyperphenylalaninemia(HPA) in some regions of Sichuan, so as to provide basis for genetic diagnosis, prenatal diagnosis and genetic counseling of patients. Method PAH, PTS, QDPR, PCBD1, SPR and GCH1 genes of 43 HPA children were analyzed by next-generation sequencing technology (NGS). Results Totally 35 cases with PAH gene mutation and 8 cases with PTS gene mutation were detected.The most common mutations of PAH in the top three were p.R243Q, p.R241C and p.Ex6-96A>G.Finally 28 mutations (39.4%) were identified in exon 7.The p.G272V mutation of PAH had not been reported previously.The p.P87S, p.Y27Rfs*8, p.D96N and p.V56M mutations were the most common mutations of PTS.And 8 mutations (50.0%) were identified in exon 5.The p.T58R mutation of PTS was not reported previously. Conclusion The mutational spectrum of HPA-related genes in some regions of Sichuan is preliminarily constructed in this study, and a new mutation is detected in PAH and PTS respectively, which will provide reliable basis for genetic diagnosis and genetic counseling of patients with HPA in this region.
关键词
高苯丙氨酸血症 /
苯丙氨酸羟化酶 /
6-丙酮酰四氢蝶呤合成酶 /
突变
Key words
hyperphenylalaninemia /
phenylalanine hydroxylase /
6-pyruvoyl tetrahydropterin synthase /
gene mutation
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参考文献
[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.
[2] 陈挺,赵正言,蒋萍萍,等.高苯丙氨酸血症表型与基因型研究进展[J].浙江大学学报:医学版,2018, 47(3):219-226.
[3] 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.
[4] Almannai M,Felemban R,Saleh MA, et al.6-pyruvoyltetrahydropterin synthase deficiency:review and report of 28 arab subjects[J].Pediatr Neurol,2019,96:40-47.
[5] 赵正言.新生儿遗传代谢筛查进展[J].中国实用儿科杂志,2014,29(8):586-589.
[6] 苏润,朱琳,林壹明,等.福建泉州地区高苯丙氨酸血症相关基因变异特征的研究[J].中华医学遗传学杂志,2019,36(11):1062-1066.
[7] 杨丽涓,欧明才,张钰,等.四川片区5 1万余例新生儿苯丙酮尿症筛查分析[J].中国妇幼健康研究,2019,30(11):1385-1388.
[8] 罗静思,谢波波,范歆,等.广西地区苯丙氨酸羟化酶基因突变谱和新突变[J].中华实用儿科临床杂志,2019,34(6):443-448.
[9] 唐新华,陈红,章印红,等.云南地区汉族苯丙酮尿症患者苯丙氨酸羟化酶基因突变的研究[J].中华医学遗传学杂志,2015,32(2):153-157.
[10] 强荣,余伍忠,蔡娜,等.陕西地区苯丙酮尿症患儿苯丙氨酸羟化酶基因突变研究[J].中华医学遗传学杂志,2014,30(1):74-77.
[11] 闫有圣,王铮,郝胜菊,等.甘肃地区苯丙酮尿症患者苯丙氨酸羟化酶基因突变分析[J].中华医学遗传学杂志,2009,26(4):419-422.
[12] 卢超霞,高峡,王金玮,等.河北地区 55 例苯丙酮尿症患者苯丙氨酸羟化酶基因突变的检测与分析[J].中华医学杂志,2011,91(42):2971-2976.
[13] Dobrowolski SF, Heintz C, Miller T, et al.Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population[J].Mol Genet Metab, 2011,102(2):116-121.
[14] Okano Y, Kudo S, Nishi Y, et al.Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalaninehydroxylase deficiency in Japan[J].Hum Genet, 2011,56(4):306-312.
[15] Thony B, Leimbacher W, Burgisser D,et al.Human 6-pyruvoyl-tetrahdropterin synthase:cDNA cloning and heterologous expression of the recombinant enzyme[J].Biochem Biophys Res Commun,1992,189(3):1437-1443.
[16] 刘宁,赵德华,李晓乐,等.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.
[17] 顾梅青,叶军,邱文娟,等.55例6-丙酮酰四氢蝶呤合成酶缺乏症基因突变分析[J].中华医学遗传学杂志,2009,26(2):183-186.
[18] Wang R,Shen N,Ye J,et al.Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population[J].Clin Chim Acta,2018,481:132-138.
[19] Chiu YH,Chang YC,Chang YH,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.
[20] Stojiljkovic M, Klaassen K, Djordjevic M, et al.Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia[J].J Pediatr Endocrinol Metab, 2015,28(3-4):477-480.
[21] Leuzzi V, Carducci CA, Carducci CL, et al.Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency[J].Clin Genet, 2010,77(3):249-257.
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