线粒体DNA耗竭综合征1例临床特点和DGUOK基因突变分析

邓梅; 林伟霞; 郭丽; 张占会; 宋元宗

doi:10.7499/j.issn.1008-8830.2016.06.015

PDF(2645 KB)

HTML

中国当代儿科杂志 ›› 2016, Vol. 18 ›› Issue (6) : 545-550. DOI: 10.7499/j.issn.1008-8830.2016.06.015

论著·临床研究

线粒体DNA耗竭综合征1例临床特点和DGUOK基因突变分析

邓梅¹, 林伟霞¹, 郭丽¹, 张占会², 宋元宗¹

作者信息 +

Clinical features and DGUOK mutations of an infant with mitochondrial DNA depletion syndrome

DENG Mei¹, LIN Wei-Xia¹, GUO Li¹, ZHANG Zhan-Hui², SONG Yuan-Zong¹

Author information +

文章历史 +

摘要

该文报道1例线粒体DNA耗竭综合征患儿的临床特征及DGUOK基因突变特点。患儿女,婴儿期起病,表现为肝脾肿大、肝功能异常、眼球震颤和精神运动发育迟缓等。提取患儿及其父母外周血DNA标本,采用外显子组捕获测序技术检测致病突变,并对检测到的突变进行Sanger测序验证。结果显示患儿为DGUOK基因突变c.679G>A和c.817delT的复合杂合子,前一个突变来自于母亲,为已报道致病性突变;后者来自于父亲,是一个未见文献报道的新突变。该研究扩展了DGOUK基因突变谱,为患儿病因诊断及该家系的遗传咨询和产前诊断提供了分子依据。

Abstract

The aim of this study was to investigate the clinical features and DGUOK gene mutations of an infant with mitochondrial DNA depletion syndrome (MDS). The patient (more than 7 months old) manifested as hepatosplenomegaly, abnormal liver function, nystagmus and psychomotor retardation. Genetic DNA was extracted from peripheral blood samples of the patient and her parents. Targeted Exome Sequencing was performed to explore the genetic causes. Sanger sequencing was carried out to confirm the detected mutations. The sequencing results showed that the patient was a compound heterozygote for c.679G>A and c.817delT in the DGUOK gene. The former was a reportedly pathogenic missense mutation of maternal origin, while the latter, a frameshift mutation from the father, has not been described yet. The findings in this study expand the mutation spectrum of DGUOK gene, and provide molecular evidence for the etiologic diagnosis of the patient as well as for the genetic counseling and prenatal diagnosis in the family.

导出引用

邓梅, 林伟霞, 郭丽, 张占会, 宋元宗. 线粒体DNA耗竭综合征1例临床特点和DGUOK基因突变分析[J]. 中国当代儿科杂志. 2016, 18(6): 545-550 https://doi.org/10.7499/j.issn.1008-8830.2016.06.015

DENG Mei, LIN Wei-Xia, GUO Li, ZHANG Zhan-Hui, SONG Yuan-Zong. Clinical features and DGUOK mutations of an infant with mitochondrial DNA depletion syndrome[J]. Chinese Journal of Contemporary Pediatrics. 2016, 18(6): 545-550 https://doi.org/10.7499/j.issn.1008-8830.2016.06.015

参考文献

[1] Spinazzola A, Invernizzi F, Carrara F, et al. Clinical and molecular features of mitochondrial DNA depletion syndromes[J]. J Inherit Metab Dis, 2009, 32(2): 143-158.
[2] El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options[J]. Neurotherapeutics, 2013, 10(2): 186-198.
[3] Mandel H, Szargel R, Labay V, et al. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA[J]. Nat Genet, 2001, 29(3): 337-341.
[4] Salviati L, Sacconi S, Mancuso M, et al. Mitochondrial DNA depletion and dGK gene mutations[J]. Ann Neurol, 2002, 52(3): 311-317.
[5] Ji JQ, Dimmock D, Tang LY, et al. A novel c.592-4_c.592-3delTT mutation in DGUOK gene causes exon skipping[J]. Mitochondrion, 2010, 10(2): 188-191.
[6] Sezer T, Ozçay F, Balci O, et al. Novel deoxyguanosine kinase gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome[J]. J Child Neurol, 2015, 30(1): 124-128.
[7] Suomalainen A, Isohanni P. Mitochondrial DNA depletion syndromes--many genes, common mechanisms[J]. Neuromuscul Disord, 2010, 20(7): 429-437.
[8] Dimmock DP, Zhang Q, Dionisi-Vici C, et al. Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase[J]. Hum Mutat, 2008, 29(2): 330-331.
[9] Yamazaki T, Murayama K, Compton AG, et al. Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: focusing on mitochondrial DNA depletion syndrome[J]. Pediatr Int, 2014, 56(2): 180-187.
[10] Pronicka E, Węglewska-Jurkiewicz A, Taybert J, et al. Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure[J]. J Appl Genet, 2011, 52(1): 61-66.
[11] 刘志梅,方方,丁昌红,等. 二代测序在儿童线粒体病诊断中的应用[J].中华儿科杂志, 2015, 53(10): 747-753.
[12] 刘志梅,方方,丁昌红,等. SUCLA2相关脑肌病型线粒体DNA耗竭综合征一例并文献复习[J].中华儿科杂志, 2014, 52(11): 817-821.
[13] den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations[J]. Hum Genet, 2001, 109(1): 121-124.
[14] den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion[J]. Hum Mutat, 2000, 15(1): 7-12.
[15] Johansson K, Ramaswamy S, Ljungcrantz C, et al. Structural basis for substrate specificities of cellular deoxyribonucleoside kinases[J]. Nat Struct Biol, 2001, 8(7): 616-620.
[16] Eriksson S, Munch-Petersen B, Johansson K, et al. Structure and function of cellular deoxyribonucleoside kinases[J]. Cell Mol Life Sci, 2002, 59(8): 1327-1346.
[17] Lee NC, Dimmock D, Hwu WL, et al. Simultaneous detection of mitochondrial DNA depletion and single-exon deletion in the deoxyguanosine gene using array-based comparative genomic hybridisation[J]. Arch Dis Child, 2009, 94(1): 55-58.
[18] Kiliç M, Sivri HS, Dursun A, et al. A novel mutation in the DGUOK gene in a Turkish newborn with mitochondrial depletion syndrome[J]. Turk J Pediatr, 2011, 53(1): 79-82.
[19] Saada-Reisch A. Deoxyribonucleoside kinases in mitochondrial DNA depletion[J]. Nucleosides Nucleotides Nucleic Acids, 2004, 23(8-9): 1205-1215.
[20] Rötig A, Poulton J. Genetic causes of mitochondrial DNA depletion in humans[J]. Biochim Biophys Acta, 2009, 1792(12): 1103-1108.
[21] Scheers I, Bachy V, Stephenne X, et al. Risk of hepatocellular carcinoma in liver mitochondrial respiratory chain disorders[J]. J Pediatr, 2005, 146(3): 414-417.
[22] Freisinger P, Futterer N, Lankes E, et al. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations[J]. Arch Neurol, 2006, 63(8): 1129-1134.
[23] Labarthe F, Dobbelaere D, Devisme L, et al. Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency[J]. J Hepatol, 2005, 43(2): 333-341.
[24] Vu TH, Tanji K, Holve SA, et al. Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?[J]. Hepatology, 2001, 34(1): 116-120.
[25] Al-Hussaini A, Faqeih E, El-Hattab AW, et al. Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure[J]. J Pediatr, 2014, 164(3): 553-559.
[26] Dimmock DP, Dunn JK, Feigenbaum A, et al. Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency[J]. Liver Transpl, 2008, 14(10): 1480-1485.