Dataset Information

Identification of a Novel Variant in MT-CO3 Causing MELAS.

ABSTRACT: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease. Most cases of MELAS are caused by the m.3243A > G variant in the MT-TL1 gene encoding tRNALeu^(UUR). However, the genetic cause in 10% of patients with MELAS is unknown. We investigated the pathogenicity of the novel mtDNA variant m.9396G > A/MT-CO3 (p.E64K), which affects an extremely conserved amino acid in the CO3 subunit of mitochondrial respiratory chain (MRC) complex IV (CIV) in a patient with MELAS. Biochemical assays of a muscle biopsy confirmed remarkable CIV deficiency, and pathological examination showed ragged red fibers and generalized COX non-reactive muscle fibers. Transfer of the mutant mtDNA into cybrids impaired CIV assembly, followed by remarkable mitochondrial dysfunction and ROS production. Our findings highlight the pathogenicity of a novel m.9396G > A variant and extend the spectrum of pathogenic mtDNA variants.

SUBMITTER: Xu M

PROVIDER: S-EPMC8153374 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Identification of a Novel Variant in MT-CO3 Causing MELAS.

Xu Manting M Kopajtich Robert R Elstner Matthias M Wang Zhaoxia Z Liu Zhimei Z Wang Junling J Prokisch Holger H Fang Fang F

Frontiers in genetics 20210512

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease. Most cases of MELAS are caused by the m.3243A > G variant in the MT-TL1 gene encoding tRNALeu(UUR). However, the genetic cause in 10% of patients with MELAS is unknown. We investigated the pathogenicity of the novel mtDNA variant m.9396G > A/MT-CO3 (p.E64K), which affects an extremely conserved amino acid in the CO3 subunit of mitochondrial ...[more]

PMID: 34054915

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Project description:BackgroundPathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS-like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura.MethodsThe patient was an 8-year-old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS-like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole-exome sequencing (WES).ResultsWES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic.ConclusionAt present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS-like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.

Dataset Information

Identification of a Novel Variant in MT-CO3 Causing MELAS.

Publications

Identification of a Novel Variant in <i>MT-CO3</i> Causing MELAS.

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