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Analysis of a family with mitochondrial trifunctional protein deficiency caused by HADHA gene mutations

  • Authors:
    • Jinling Yang
    • Dejian Yuan
    • Xiaohui Tan
    • Yexi Zeng
    • Ning Tang
    • Dayu Chen
    • Jianqiang Tan
    • Ren Cai
    • Jun Huang
    • Tizhen Yan
  • View Affiliations / Copyright

    Affiliations: 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, Newborn Screening Center, Huizhou Second Maternity and Child Health Care Hospital, Huizhou, Guangdong 516001, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 47
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    Published online on: December 8, 2021
       https://doi.org/10.3892/mmr.2021.12563
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Abstract

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 HADHA gene, encoding the α‑subunit of a trifunctional protease, or in the HADHB gene, encoding the β‑subunit of a trifunctional protease. To the best of our knowledge, only two cases of families with MTPD due to HADHB gene mutations have been reported in China, and the HADHA gene mutation has not been reported in a Chinese family with MTPD. The present study reported the clinical characteristics and compound heterozygous HADHA 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 HADHA 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 HADHA 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 HADHA gene underlying this disorder in China. The clinical phenotypes of the two heterozygous variants of the HADHA gene are non‑lethal. The present study may improve understanding of the HADHA gene mutation spectrum and clinical phenotype in the Chinese population.
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Copy and paste a formatted citation
Spandidos Publications style
Yang J, Yuan D, Tan X, Zeng Y, Tang N, Chen D, Tan J, Cai R, Huang J, Yan T, Yan T, et al: Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations. Mol Med Rep 25: 47, 2022.
APA
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D. ... Yan, T. (2022). Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations. Molecular Medicine Reports, 25, 47. https://doi.org/10.3892/mmr.2021.12563
MLA
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D., Tan, J., Cai, R., Huang, J., Yan, T."Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations". Molecular Medicine Reports 25.2 (2022): 47.
Chicago
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D., Tan, J., Cai, R., Huang, J., Yan, T."Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations". Molecular Medicine Reports 25, no. 2 (2022): 47. https://doi.org/10.3892/mmr.2021.12563
Copy and paste a formatted citation
x
Spandidos Publications style
Yang J, Yuan D, Tan X, Zeng Y, Tang N, Chen D, Tan J, Cai R, Huang J, Yan T, Yan T, et al: Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations. Mol Med Rep 25: 47, 2022.
APA
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D. ... Yan, T. (2022). Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations. Molecular Medicine Reports, 25, 47. https://doi.org/10.3892/mmr.2021.12563
MLA
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D., Tan, J., Cai, R., Huang, J., Yan, T."Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations". Molecular Medicine Reports 25.2 (2022): 47.
Chicago
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D., Tan, J., Cai, R., Huang, J., Yan, T."Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations". Molecular Medicine Reports 25, no. 2 (2022): 47. https://doi.org/10.3892/mmr.2021.12563
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