2 research outputs found
Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency
Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients
Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca<sup>2+</sup>
Mutations in
C19orf12
have been identified in patients affected by Neurodegeneration
with Brain Iron Accumulation (NBIA), a clinical entity characterized by iron accumulation
in the basal ganglia. By using western blot analysis with specific antibody and confocal
studies, we showed that wild-type C19orf12 protein was not exclusively present in
mitochondria, but also in the Endoplasmic Reticulum (ER) and MAM (Mitochondria
Associated Membrane), while mutant C19orf12 variants presented a different localization.
Moreover, after induction of oxidative stress, a GFP-tagged C19orf12 wild-type protein
was able to relocate to the cytosol. On the contrary, mutant isoforms were not able
to respond to oxidative stress. High mitochondrial calcium concentration and increased
H
2
O
2
induced apoptosis were found in fibroblasts derived from one patient as compared
to controls. C19orf12 protein is a 17 kDa mitochondrial membrane-associated protein
whose function is still unknown. Our
in silico
investigation suggests that, the glycine
zipper motifs of C19orf12 form helical regions spanning the membrane. The N- and
C-terminal regions with respect to the transmembrane portion, on the contrary, are
predicted to rearrange in a structural domain, which is homologs to the N-terminal
regulatory domain of the magnesium transporter MgtE, suggesting that C19orf12 may
act as a regulatory protein for human MgtE transporters. The mutations here described
affect respectively one glycine residue of the glycine zipper motifs, which are involved in
dimerization of transmembrane helices and predicted to impair the correct localization
of the protein into the membranes, and one residue present in the regulatory domain,
which is important for protein-protein interaction