Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood

Abstract

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy

“…For the RES cohort, WES was performed at the Wellcome Trust Sanger Institute as part of the EuroEPINOMICS-RES project with the Illumina TruSeq DNA Sample Preparation Kit, the Agilent Technologies SureSelect Human All Exon 50Mb Kit, and the Illumina HiSeq2000 according to the manufacturers' protocols and as previously described. 12,22,23 For the DFG cohort, WES was performed at the Institute of Clinical Molecular Biology at the University of Kiel and the Cologne Center for Genomics with NimbleGen SeqCap EZ Human Exome Library v2.0, Nextera Rapid Capture Exome, Nextera Rapid Capture Expanded Exome, Agilent SureSelect Human All Exon V5, and Agilent SureSelect Human All Exon 50Mb. For the GRIN cohort, WES was performed at the Broad Institute with the Nextera Rapid Capture Exome kit.…”

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

“…PITRM1 is also involved in processing frataxin, leading to reduced levels of mature frataxin in case of mutant PITRM1 , thus demonstrating a link to FA pathophysiology. Biallelic mutations in PMPCA and PMPCB cause neurodegeneration and cerebellar atrophy (Jobling et al, 2015;Vö gtle et al, 2018). PMPCA and PMPCB form the mitochondrial processing pepti-dase (MPP), an enzyme responsible for the cleavage mitochondrial targeting peptide signal ( Figure 3B).…”

“…In S. cerevisiae, PMPCB variants resulted in severe growth and MPP processing defects, leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of Fe-S clusters. Patients with PMPCB mutations had decreased activity in Fe-S cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes, again pointing to substantial overlap with FA pathogenesis (Vö gtle et al, 2018). Mutations in POLG, the nuclear-encoded catalytic subunit of the mtDNA polymerase (responsible for mtDNA replication and repair) ( Figure 5), can present as ARCA (Coutelier et al, 2018).…”

Whole‐exome and HLA sequencing in Febrile infection‐related epilepsy syndrome

“…based on consensus criteria, 14 Bioinformatic analysis for exome and HLA sequencing Exome data were analyzed through a bioinformatic pipeline as previously described. 16,17 Analysis for pathogenic variants in genetic etiologies for human epilepsies was performed according to criteria of the American College of Medical Genetics and Genomics (ACMG). 18 HLA imputation was performed using HLAscan, including 29 cases and 529 controls of European ancestry.…”