NFU1 gene mutation and mitochondrial disorders

Abstract

Mitochondrial respiratory chains consist of approximately 100 structural proteins. Thirteen of these structural proteins are encoded by mitochondrial DNA (mtDNA), and the others by nuclear DNA (nDNA). Mutation in any of the mitochondrial structural-protein related genes, regardless of whether they are in the nDNA or mtDNA, might cause mitochondrial disorders. In the recent past, new nuclear genes required for assembly, maintenance, and translation of respiratory chain proteins have been found. Mutation in these genes might also cause mitochondrial disorders (MD). NFU1 gene is one of such genes and has a role in the assembly of iron-sulfur cluster (ISC). ISCs are included in a variety of metalloproteins, such as the ferredoxins, as well as in enzymatic reactions and have been first identified in the oxidation-reduction reactions of mitochondrial electron transport. It is important to be aware of NFU1 gene mutations that may cause severe mitochondrial respiratory chain defects, mitochondrial encephalomyopathies and death, early in life.

Hereditary Disorders and Human Mutations of Iron-Sulfur Assembly Genes

“…Thus, NFU1 mutation appears to have some effect on Fe-S enzyme lipoic acid synthase (LAS). In conclusion, NFU1 is an ISC assembly protein, and there is strong evidence that LAS deficiency is important in NFU1 mutation-related disease [31].…”

“…Complex I, II, and III of oxidative phosphorylation have multiple Fe-S clusters. Therefore, any deficiency in these clusters causes dysfunctions of respiratory chain complexes [31]. Previous studies showed that the function of the NFU1 has been associated by the fatal mitochondrial disease, multiple mitochondrial dysfunctions syndrome 1 (MMDS1) [30].…”

“…Previous studies showed that the function of the NFU1 has been associated by the fatal mitochondrial disease, multiple mitochondrial dysfunctions syndrome 1 (MMDS1) [30]. Patients with NFU1 mutations usually manifest feeding difficulty, weakness, lethargy, and decreasing responsiveness within a few days after birth and a few had epileptic seizures [31]. It has been shown that the patients with mutations in the NFU1 gene have similar biochemical features to that seen in patients with lipoic acid defects.…”

NFU1-Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy

“…NFU1-related disorders represent an autosomal recessive expanding group of neurological syndromes, commonly referred to as MMDS type 1 (OMIM #605711), resulting from homozygous or compound heterozygous mutations in the NFU1 gene (2p13.3), encoding an iron-sulfur cluster protein involved in normal biosynthesis of lipoic acid and indirectly involved with the stability of mitochondrial respiratory chain complexes I and II. 3,7,8 Most cases generally have a neonatal onset of muscle weakness, early neuropsychomotor development delay, epileptic encephalopathy with severe compromise during intercurrent illnesses, and neuroimaging studies disclosing severe cystic and cavitating leukoencephalopathy resulting from white matter necrosis and spongiform neurodegeneration. Systemic features include failure to thrive, pulmonary hypertension, obstructive vasculopathy, and very early-onset acute respiratory failure.…”

Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension

“…Similarly, multiple mitochondrial dysfunctions syndromes are a rare class of disorders found to cause early-onset, autosomal recessive pHTN through inhibition of multiple mitochondrial processes. Multiple mitochondrial dysfunctions syndrome 1 (MMDS1-MIM #605711) is due to biallelic pathogenic variants in NFU1 (MIM #608100), a nuclear gene that encodes a member of the iron-sulfur cluster assembly complex (Kurt, Kurt, Aydin, Agilli, & Aydin, 2016;Lebigot et al, 2017;Melber et al, 2016).…”