Please wait a minute...
J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (5): 574-580    DOI: 10.3785/j.issn.1008-9292.2020.10.04
    
Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1
SHEN Yaping1(),YAN Kai2,DONG Minyue2,YANG Rulai1,HUANG Xinwen1,*()
1. Department of Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Medical Centre for Children, Hangzhou 310052, China
2. Department of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou 310006, China
Download: HTML( 11 )   PDF(8178KB)
Export: BibTeX | EndNote (RIS)      

Abstract  

Objective: To analyze the clinical phenotype and genetic characteristics of a family with combined oxidative phosphorylation deficiency 1 (COXPD-1). Methods: The whole exome sequencing was performed in parents of the proband; and the genetic defects were verified by Sanger sequencing technology in the dried blood spot of the proband, the amniotic fluid sample of the little brother of proband, and the peripheral blood of the parents. Results: Whole exome sequencing and Sanger validation showed compound heterozygous mutations of GFM1 gene c.688G>A(p.G230S) and c.1576C>T (p.R526X) in both the proband and her little brother, and the c.1576C>T of GFM1 variant was first reported. The two patients were died in early infancy, and presented with metabolic acidosis, high lactic acid, abnormal liver function, feeding difficulties, microcephaly, development retardation and epilepsy. Conclusion: GFM1 gene c.688G>A and c.1576C>T compound heterozygous mutations are the cause of this family of COXPD-1.



Key wordsCongenital, hereditary, and neonatal diseases and abnormalities      Combined oxidative phosphorylation deficiency 1      GFM1 gene      Metabolic acidosis      Whole exome sequencing     
Received: 12 May 2020      Published: 19 November 2020
CLC:  R394.3  
Corresponding Authors: HUANG Xinwen     E-mail: 6517066@zju.edu.cn;6305022@zju.edu.cn
Cite this article:

SHEN Yaping,YAN Kai,DONG Minyue,YANG Rulai,HUANG Xinwen. Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1. J Zhejiang Univ (Med Sci), 2020, 49(5): 574-580.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.10.04     OR     http://www.zjujournals.com/med/Y2020/V49/I5/574


联合氧化磷酸化缺陷症1型一家系临床表型及GFM1基因突变分析

目的: 分析一个联合氧化磷酸化缺陷症1型家系的临床表型及遗传学特点,明确其遗传学病因。方法: 对先证者父母外周血DNA行全外显子组测序,对先证者(已故)干血斑标本、胎儿(先证者弟弟)羊水和先证者父母亲外周血行Sanger验证。结果: 全外显子组测序和Sanger测序显示,先证者及其弟弟均为GFM1基因c.688G>A(p.G230S)与c.1576C>T(p.R526X)复合杂合突变,其中c.1576C>T系首次报道。先证者及其弟弟出生后均出现代谢性酸中毒、高乳酸血症、肝功能异常、喂养困难、小头畸形、生长发育落后、癫痫等临床表现,均在婴儿早期死亡。结论: GFM1基因c.688G>A与c.1576C>T复合杂合突变是导致该家系联合氧化磷酸化缺陷症1型的遗传学原因。


关键词: 先天性遗传性新生儿疾病和畸形,  联合氧化磷酸化缺陷症1型,  GFM1基因,  代谢性酸中毒,  全外显子组测序 
Fig 1 Sequencing results of GFM1 gene in this combined oxidative phosphorylation deficiency 1 family
Fig 2 Cranial MRI of the child (proband's brother) with combined oxidative phosphorylation deficiency 1
Fig 3 Long range electroencephalography of the child (proband's brother) with combined oxidative phosphorylation deficiency 1
编号 核苷酸改变 氨基酸改变 外显子位置 突变类型 等位基因突变个数 等位基因突变频率 参考文献序号
1 c.100C>T p.R34X 2 无义 1 0.016 18
2 c.130_137delGAAAAAATinsAAAAAAAA p.E44_I46delinsKKK 2 插入缺失 4 0.065 12
3 c.139C>T p.R47X 2 无义 1 0.016 8
4 c.170C>A p.S57Y 2 错义 1 0.016 15
5 c.238A>G p.K80E 3 错义 1 0.016 17
6 c.248A>T p.D83V 3 错义 1 0.016 18
7 c.521A>G p.N174S) 4 错义 4 0.065 6
8 c.539delG p.G180Afs*11 4 移码 1 0.016 9
9 c.688G>A p.G230S 5 错义 5 0.081 9
10 c.689+908G>A 不造成氨基酸改变,但可能影响蛋白表达 5 内含子 2 0.032 14
11 c.748C>T p.R250W 6 错义 5 0.081 1
12 c.720delT p.E241NfsX1 6 移码 2 0.032 11
13 c.910A>G p.K304E 7 错义 1 0.016 11
14 c.958C>G p.P320A 7 错义 1 0.016 18
15 c.961T>C p.S321P 7 错义 2 0.032 7
16 c.964G>A p.E322K 7 错义 1 0.016 12
17 c.1149_1160del p.I384_T387del 9 非移码 1 0.016 18
18 c.1193T>C p.L398P 9 错义 2 0.032 10
19 c.1297_1300del p.D433Kfs*20 10 移码 1 0.016 18
20 c.1404delA p.G469Vfs*84 12 移码 2 0.032 12
21 c.1487T>G p.M496R 12 错义 1 0.016 8
22 c.1546T>C p.C516R 13 错义 1 0.016 18
23 c.1571C>T p.A524V 13 错义 1 0.016 18
24 c.1576C>T p.R526X) 13 无义 2 0.032 本文资料
25 c.1655T>G p.V552G 14 错义 1 0.016 12
26 c.1686delG p.D563Tfs*24 14 移码 2 0.032 16
27 c.1765-2_1765-1delAG p.G589 15 错义 2 0.032 7
28 c.1822C>T p.R608W 15 错义 1 0.016 18
29 c.1922C>A p.A641E 16 错义 1 0.016 18
30 c.2011C>T p.R671C 16 错义 11 0.177 12
31 exon14-18dup 不造成氨基酸改变,但可能影响蛋白表达 14~18 重复 1 0.016 18
Tab 1 The allele mutation frequency of GFM1 gene in patients with combined oxidative phosphorylation deficiency 1
[1]   SMITS P , ANTONICKA H , VAN HASSELT P M et al. Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle[J]. Eur J Hum Genet, 2011, 19 (3): 275- 279
doi: 10.1038/ejhg.2010.208
[2]   RICHARDS S , AZIZ N , BALE S et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17 (5): 405- 424
doi: 10.1038/gim.2015.30
[3]   GAO J , YU L , ZHANG P et al. Cloning and characterization of human and mouse mitochondrial elongation factor G, GFM and Gfm, and mapping of GFM to human chromosome 3q25.1-q26.2[J]. Genomics, 2001, 74 (1): 109- 114
doi: 10.1006/geno.2001.6536
[4]   SMITS P , SMEITINK J , VAN DEN HEUVEL L . Mitochondrial translation and beyond:processes implicated in combined oxidative phosphorylation deficiencies[J]. J Biomed Biotechnol, 2010, 2010 737385
doi: 10.1155/2010/737385
[5]   KOSCIELNY G , YAIKHOM G , IYER V et al. The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data[J]. Nucleic Acids Res, 2014, 42 (Database issue): D802- D809
doi: 10.1093/nar/gkt977
[6]   COENEN M J , ANTONICKA H , UGALDE C et al. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency[J]. N Engl J Med, 2004, 351 (20): 2080- 2086
doi: 10.1056/NEJMoa041878
[7]   ANTONICKA H , SASARMAN F , KENNAWAY N G et al. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1[J]. Hum Mol Genet, 2006, 15 (11): 1835- 1846
doi: 10.1093/hmg/ddl106
[8]   VALENTE L , TIRANTI V , MARSANO R M et al. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu[J]. Am J Hum Genet, 2007, 80 (1): 44- 58
doi: 10.1086/510559
[9]   BALASUBRAMANIAM S , CHOY Y S , TALIB A et al. Infantile progressive hepatoencephalomyopathy with combined OXPHOS deficiency due to mutations in the mitochondrial translation elongation factor gene GFM1[J]. JIMD Rep, 2012, 5 113- 122
doi: 10.1007/8904_2011_107
[10]   GALMICHE L , SERRE V , BEINAT M et al. Toward genotype phenotype correlations in GFM1 mutations[J]. Mitochondrion, 2012, 12 (2): 242- 247
doi: 10.1016/j.mito.2011.09.007
[11]   CALVO S E , COMPTON A G , HERSHMAN S G et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing[J]. Sci Transl Med, 2012, 4 (118): 118ra10
doi: 10.1126/scitranslmed.3003310
[12]   RAVN K , SCH?NEWOLF-GREULICH B , HANSEN R M et al. Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations[J]. Mol Genet Metab Rep, 2015, 3 5- 10
doi: 10.1016/j.ymgmr.2015.01.004
[13]   BRITO S , THOMPSON K , CAMPISTOL J et al. Corrigendum:Long-term survival in a child with severe encephalopathy, multiple respiratory chain deficiency and GFM1 mutations[J]. Front Genet, 2015, 6 254
doi: 10.3389/fgene.2015.00254
[14]   SIMON M T , NG B G , FRIEDERICH M W et al. Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency[J]. Mitochondrion, 2017, 34 84- 90
doi: 10.1016/j.mito.2017.02.004
[15]   KOHDA M, TOKUZAWA Y, KISHITA Y, et al. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies[J/OL]. PLoS Genet, 2016, 12(1): e1005679. DOI: 10.1371/journal.pgen.1005679.
[16]   尤艺杰, AGNèSRotig, 王建设 . GFM1突变所致儿童急性肝衰竭1例:质疑GFM1错义突变位置决定临床表型[J]. 中国循证儿科杂志, 2016, 11 (5): 369- 372
YOU Yijie , AGNèS Rotig , WANG Jianshe . Acute liver failure caused by GFM1 mutations in a child:the relationship between GFM1 missense mutation and the peripheral amino acid and the change of clinical phenotype[J]. Chinese Journal of Evidence Based Pediatrics, 2016, 11 (5): 369- 372
doi: 10.3969/j.issn.1673-5501.2016.05.011
[17]   NASR E N , MIKKILINENI S , HEWSON S et al. Expansion of the known phenotype for mitochondrial translation elongation factor G1(EGF1) due to GFM1 mutations[J]. Clinical Biochemistry, 2014, 47 (15): 144
doi: 10.1016/j.clinbiochem.2014.07.060
[1] HU Gang, LIU Bei, CHEN Min, QIAN Yeqing, DONG Minyue. Genetic analysis and clinical phenotype of a family with lymphedema-distichiasis syndrome[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 581-585.
[2] JIN Xiaoxiao, JIN Pengzhen, YAN Kai, QIAN Yeqing, DONG Minyue. Genetic analysis of a mosaic case with low proportion mutation of TSC2 gene[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 586-590.