Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

“…Adverse consequences are also associated with lower than normal CoA levels. Decreased synthesis of this cofactor in the nervous system is associated with a rare neurological disorder in humans (11,12), while decreased synthesis of CoA in the liver leads to fasting hypoglycemia and hepatic triglyceride accumulation (13). Dynamic regulation of CoA within the normal physiological range is important to support the metabolic reprogramming that underlies the capacity to respond to changes in the metabolic state.…”

Neurodegenerations with Brain Iron Accumulation

“…COASY-associated neurodegeneration (CoPAN) is very rare but pathophysiologically closely related to PKAN. CoPAN is due to mutations in the CoA synthase (COASY) gene [5]. Similarly to PKAN, it presents with early-onset gait difficulty and learning disabilities, followed by generalized pyramidal (spastic tetraparesis) and extrapyramidal features (bradykinesia, generalized dystonia).…”

“…PANK2 regulates the first step and COASY the last two steps in CoA synthesis. [5] Both, PANK2 and COASY, are mainly targeted to mitochondria and studies functional suggest disease that pathophysiology may relate to dysfunction of cellular energy metabolism.…”

Niemann-Pick’s disease type B and brain iron accumulation

“…The list of NBIAs is continuously expanding. Besides PKAN caused by mutations in the PANK2 gene, [1,2] the best characterized subtypes include MPAN with mutations/deletions in the c19orf12 gene, [7][8][9] the PLA2G6 Associated Neurodegeneration (PLAN) with mutations in the PLA2G6 gene, [10] the Coasy Protein Associated Neurodegeneration (CoPAN) with mutations in the Coasy gene, [11] and the Beta-Propeller Protein Associated Neurodegeneration (BPAN) with mutations in the WDR45 gene. [12] A shared feature of these diseases is brain iron accumulation that is likely secondary to abnormalities in lipid metabolism and autophagy.…”