ABSTRACT
We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months. Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low. Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G > T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545 + 5G > A) mutation. The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases. Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished. In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation. Similar biochemical effects were observed in Saccharomyces cerevisiae upon deletion of NFU1, resulting in lower lipoylation and SDH activity. Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins.
Subject(s)
Carrier Proteins , Mitochondrial Diseases/genetics , Mitochondrial Proteins , Mutation, Missense , Saccharomyces cerevisiae Proteins , Amino Acid Oxidoreductases/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Chromosomes, Human, Pair 2/genetics , Female , HeLa Cells , Homozygote , Humans , Hypertension/genetics , Infant , Iron-Sulfur Proteins/genetics , Iron-Sulfur Proteins/metabolism , Male , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Multienzyme Complexes/metabolism , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Sequence Homology, Amino Acid , Succinate Dehydrogenase/metabolism , Sulfurtransferases/metabolism , Thioctic Acid/metabolism , Transferases/metabolismSubject(s)
Corneal Opacity/drug therapy , Iduronidase/therapeutic use , Mucopolysaccharidosis I/drug therapy , Mucopolysaccharidosis I/physiopathology , Vision Disorders/drug therapy , Adult , Corneal Opacity/genetics , Corneal Opacity/physiopathology , Humans , Male , Mucopolysaccharidosis I/genetics , Recombinant Proteins/therapeutic use , Vision Disorders/genetics , Vision Disorders/physiopathology , Visual Acuity/drug effectsABSTRACT
Alexander disease is a neurodegenerative disorder characterized by macrocephaly and progressive demyelination with frontal lobe preponderance. The infantile form, the most frequent variant, appears between birth and 2 years of age and involves a severe course with a rapid neurologic deterioration. Although magnetic resonance imaging is useful for diagnosis, currently diagnosis is confirmed by the finding of missense mutation in the glial fibrillary acidic protein (GFAP) gene. This case reports a female who presented at the age of 5 months with refractory epilepsy and hypotonia. Laboratory examinations, muscle biopsy examination, and energetic metabolic study in muscle indicated increased concentrations of lactate, mitochondria with structural abnormalities, and decreased cytochrome-c oxidase activity respectively. Later, both clinical course and magnetic resonance findings were compatible with Alexander disease, which was confirmed by the finding of a novel glial fibrillary acidic protein gene mutation.
