Novel homozygous mutation in the FBXL4 gene is associated with mitochondria DNA depletion syndrome-13

Abstract

Background: Mitochondrial DNA depletion syndrome-13 (MTDPS13) is caused by mutations in FBXL4 (F-box and leucine-rich repeat protein 4), a nuclear gene encoding an F-box protein that plays a role in maintaining mtDNA integrity and stability. Methods: We identified a novel homozygous FBXL4 gene mutation, c.993dupA (p.L332Tfs*3), in a 1-year-old girl of Han Chinese descent. We performed three-dimensional protein structural analysis and targeted mtDNA nextgeneration sequencing. We analysed FBXL4 expression and mitochondrial DNA level, and reviewed mutations reported in FBXL4-related literature. Results: This mutation resulted in premature termination of translation and loss of 288 amino acids from Cterminus. A three-dimensional structural analysis revealed that conserved LRR domains were lost in mutant FBXL4 protein, which likely affected its ability to form protein-protein interactions. There were no differences in FBXL4 mRNA expression levels between the patient and her parents. There were no mtDNA mutations in either the patient or her parents. However, ND1/GAPDH ratio in lymphocytes and urine, which represents mtDNA/ nuclear DNA ratio, showed that the number of mitochondrial genomes was significantly lower in the patient than in her parents or wild-type subjects. Conclusion: Homozygous FBXL4 gene mutation, c.993dupA, can cause mitochondrial dysfunction, and LRR region is especially important for FBXL4 protein function.

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a

“…Likewise, absence of FBXL4 leads to aberrant changes in mitochondrial proteins and mitochondrial function through degradation of mitochondria [ 19 ]. Examination of human genes associated with encephalopathy also revealed an etiological role for mutant FBXL4 in mitochondrial swelling and mitochondrial respiratory dysfunction [ 52 , 53 ]. Mitochondrial phenotypic changes included mitochondrial fragmentation, decreased basal and maximal respiration, impaired survival under obligate aerobic respiration, and lost mitochondrial inner membrane potential under FBXL4 deficiency [ 54 ].…”

“…FBXL4 comprises canonical FBXL functional domains [ 63 ]. Importantly, FBXL4 contains a mitochondrial localization sensor, allowing its colocalization with mitochondrial proteins [ 53 ]. In our hands, FBXL4 interacted with Drp1 through F-box domain on FBXL4 to speed up Drp1 ubiquitination/degradation to keep mitochondrial fission in check.…”

Mitochondrial quality control alterations and placenta-related disorders

“…F-Box and Leucine-rich repeat protein 4 is a nuclear-encoded mitochondrial protein that is in the intermembrane space. F-Box and Leucine-rich repeat protein 4 may also play a role in mitochondrial fusion by interacting with and regulating mitochondrial fusion proteins ( Wang et al, 2020 ). Proteins involved in mediating mitochondrial fission include dynamin-related protein 1 (Drp1), fission protein 1, and mitochondrial dynamic proteins MiD49 and MiD51 ( Serasinghe and Chipuk, 2017 ).…”

Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease

“…SLC25A4 c.239G>A was found in a case of mitochondrial exhaustion syndrome (MTDPS12) with epileptic encephalopathy. The patient was admitted to hospital due to continuous facial and limb spasm, accompanied by mild respiratory failure ( 110 ). A frame-shift null mutation (c.523delC, p.Q175RfsX38) of SLC25A4 resulted in autosomal recessive myopathy and cardiomyopathy.…”

“…The mutations can lead to mitochondrial exhaustion syndrome 13 (MTDPS13) of cerebral muscular disease type, which is often manifested as decreased muscle tone, difficulty in eating, delayed nerve development, brain atrophy and other symptoms, accompanied by increased blood lactic acid level ( 137 , 138 ). Wang et al found a novel FBXL4 frameshift mutation (c.993dupA) in a Han Chinese patient, leading to the premature termination of protein synthesis and defects at the protein level ( 110 ). Ballout et al reported the first case of MTDPS13 in Lebanon.…”