Newborn Screening Center, Department of Medical Genetics, Key Laboratory of Prevention and Control of Birth Defects, Liuzhou Maternity and Child Health Care Hospital, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, Guangxi 545000, P.R. China.
School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Mol Med Rep. 2022 Feb;25(2). doi: 10.3892/mmr.2021.12563. Epub 2021 Dec 8.
Mitochondrial trifunctional protein (MTP) deficiency (MTPD; MIM 609015) is a metabolic disease of fatty acid oxidation. MTPD is an autosomal recessive disorder caused by mutations in the gene, encoding the α‑subunit of a trifunctional protease, or in the gene, encoding the β‑subunit of a trifunctional protease. To the best of our knowledge, only two cases of families with MTPD due to gene mutations have been reported in China, and the gene mutation has not been reported in a Chinese family with MTPD. The present study reported the clinical characteristics and compound heterozygous gene mutations of two patients with MTPD in the Chinese population. The medical history, routine examination data, blood acyl‑carnitine analysis results, results of pathological examination after autopsy and family pedigree map were collected for patients with MTPD. The gene was analyzed by Sanger sequencing or high‑throughput sequencing, the pathogenicity of the newly discovered variant was interpreted by bioinformatics analysis, and the function of the mutated protein was modeled and analyzed according to 3D structure. The two patients with MTPD experienced metabolic crises and died following an infectious disease. Lactate dehydrogenase, creatine kinase (CK), CK‑MB and liver enzyme abnormalities were observed in routine examinations. Tandem mass spectrometry revealed that long‑chain acyl‑carnitine was markedly elevated in blood samples from the patients with MTPD. The autopsy results for one child revealed fat accumulation in the liver and heart. Next‑generation sequencing detected compound heterozygous c.703C>T (p.R235W) and c.2107G>A (p.G703R) mutations in the gene. The mother did not have acute fatty liver during pregnancy with the two patients. Using amniotic fluid prenatal diagnostic testing, the unborn child was confirmed to carry only c.2107G>A (p.G703R). Molecular mechanistic analysis indicated that the two variants affected the conformation of the α‑subunit of the MTP enzyme complex, and consequently affected the stability and function of the enzyme complex. The present study comprehensively analyzed the cases, including exome sequencing and protein structure analysis and, to the best of our knowledge, describes the first observation of compound heterozygous mutations in the gene underlying this disorder in China. The clinical phenotypes of the two heterozygous variants of the gene are non‑lethal. The present study may improve understanding of the gene mutation spectrum and clinical phenotype in the Chinese population.
线粒体三功能蛋白（MTP）缺乏症（MTPD；MIM 609015）是一种脂肪酸氧化的代谢疾病。MTPD 是一种常染色体隐性遗传疾病，由 基因或 基因突变引起，分别编码三功能蛋白酶的α亚基和β亚基。据我们所知，在中国仅报道了两例由于 基因突变导致的 MTPD 家系，且尚未在 MTPD 的中国家系中报道过 基因突变。本研究报道了中国人群中 2 例 MTPD 患者的临床特征和复合杂合 基因突变。收集 MTPD 患者的病史、常规检查数据、血酰基肉碱分析结果、尸检后病理检查结果和家系图谱。通过 Sanger 测序或高通量测序分析 基因，采用生物信息学分析解释新发现的变异的致病性，并根据 3D 结构对突变蛋白的功能进行建模和分析。两名 MTPD 患者均因感染性疾病而发生代谢危象并死亡。常规检查发现乳酸脱氢酶、肌酸激酶（CK）、CK-MB 和肝酶异常。串联质谱分析显示，MTPD 患者的血液样本中长链酰基肉碱显著升高。一名患儿的尸检结果显示肝脏和心脏脂肪堆积。下一代测序检测到 基因的复合杂合 c.703C>T（p.R235W）和 c.2107G>A（p.G703R）突变。两名患儿的母亲在怀孕期间均未出现急性脂肪肝。通过羊水产前诊断检测，证实未出生的孩子仅携带 c.2107G>A（p.G703R）。分子机制分析表明，这两种变异影响了 MTP 酶复合物的α亚基构象，进而影响了酶复合物的稳定性和功能。本研究全面分析了病例，包括外显子组测序和蛋白质结构分析，据我们所知，这是首次在中国报道该疾病由 基因复合杂合突变引起。 基因的两种杂合变异的临床表型是非致死性的。本研究可能有助于提高对中国人群中 基因突变谱和临床表型的认识。
