Mitochondrial <i>PITRM1</i> peptidase loss-of-function in childhood cerebellar atrophy.

Abstract

To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy. Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (<i>PITRM1</i>) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in <i>PITRM1</i> protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same <i>PITRM1</i> mutation on a shared haplotype. <i>PITRM1T931M</i> carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. <i>PITRM1</i> is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the <i>PITRM1T931M</i> protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids. <i>PITRM1T931M</i> results in childhood-onset recessive cerebellar pathology. Severity of <i>PITRM1</i>-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.