[P1-159] Mutations in IBA57 cause aberrant NFU1 function in the iron-sulfur cluster assembly system, leading to cavitating leukoencephalopathy
[Objective] Progressive cavitating leukoencephalopathy (PCL) is a neurodegenerative disorder characterized by patchy leukoencephalopathy with cavities. We here report three Japanese PCL patients from two unrelated families that manifested episodic clinical deterioration associated with periodic paresis of the lower limbs with clinically and radiologically compatible brain involvement. The aim of this study was to determine the common molecular factors contributing to PCL in these cases to help resolve the underlying genotype-phenotype associations.
[Methods] We used full-exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of iron-sulfur cluster-associated factors with PCL.
[Results] Compound heterozygous mutations in the IBA57 gene were identified in both families with exome sequencing, encoding the mitochondrial iron-sulfur protein assembly factor. IBA57 protein expression was substantially decreased in the patient myoblasts and fibroblasts. Immunoblotting revealed significantly reduced expression of SDHB (a subunit of complex II), pyruvate dehydrogenase complex-E2, and α-ketotoglutarate dehydrogenase-E2 involved in lipoic acid synthetase (LIAS) in all patients. SDH activity was also clearly reduced, but its activity was ameliorated in mitochondrial fractions prepared from rescued myoblasts. In addition, NFU1 protein was significantly decreased, which dedicated iron sulfur cluster targeting factor and required assembly of lipoic acid synthetase and SDH, although no mutation in NFU1 was detected.
[Interpretation] Defects of IBA57 essentially interfere with the expression of SDHB and NFU1, and the aberrant NFU1 ultimately affects LIAS deficiency. This study provides new insights of the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism.
[Methods] We used full-exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of iron-sulfur cluster-associated factors with PCL.
[Results] Compound heterozygous mutations in the IBA57 gene were identified in both families with exome sequencing, encoding the mitochondrial iron-sulfur protein assembly factor. IBA57 protein expression was substantially decreased in the patient myoblasts and fibroblasts. Immunoblotting revealed significantly reduced expression of SDHB (a subunit of complex II), pyruvate dehydrogenase complex-E2, and α-ketotoglutarate dehydrogenase-E2 involved in lipoic acid synthetase (LIAS) in all patients. SDH activity was also clearly reduced, but its activity was ameliorated in mitochondrial fractions prepared from rescued myoblasts. In addition, NFU1 protein was significantly decreased, which dedicated iron sulfur cluster targeting factor and required assembly of lipoic acid synthetase and SDH, although no mutation in NFU1 was detected.
[Interpretation] Defects of IBA57 essentially interfere with the expression of SDHB and NFU1, and the aberrant NFU1 ultimately affects LIAS deficiency. This study provides new insights of the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism.